Pharmaceutical compositions comprising meloxicam

ABSTRACT

Disclosed herein are compositions comprising a drug such as a triptan (e.g. rizatriptan) and/or an NSAID (e.g. meloxicam) in combination with a cyclodextrin and/or a carbonate or a bicarbonate. These compositions may be orally administered, for example, to improve the bioavailability or pharmacokinetics of the drug for the treatment of conditions such as pain.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/181,086, filed Nov. 5, 2018; which is a continuation of U.S. patentapplication Ser. No. 15/936,176, filed Mar. 26, 2018, now U.S. Pat. No.10,137,131; which is a continuation-in-part of PCT/US18/12433, filedJan. 4, 2018; which claims the benefit of U.S. Prov. Pat. App. Nos.62/442,136, filed Jan. 4, 2017; 62/504,105, filed May 10, 2017; and62/536,466, filed Jul. 25, 2017; any of the above applications, U.S.patents issued from, or U.S. publications of any of the aboveapplications are incorporated by reference in their entirety.

BACKGROUND

There continues to be a need for therapies with improved efficacy intreating pain, inflammation, and related conditions.

SUMMARY

This disclosure relates to the use of a bicarbonate and/or acyclodextrin, such as sulfobutylether β-cyclodextrin (SBEβCD), toimprove the pharmacokinetics or bioavailability of a drug, such as anonsteroidal anti-inflammatory drug (NSAID), e.g. meloxicam, a triptan,e.g. rizatriptan, or a combination thereof.

For example, some embodiments include dosage forms comprising a triptan(such as rizatriptan or frovatriptan), in combination with acyclodextrin (optionally as an inclusion complex of the triptan and thecyclodextrin), and/or a bicarbonate, and methods of treatment using thedosage form.

Some embodiments include a dosage form comprising: meloxicam; asulfobutyl ether β-cyclodextrin (SBEβCD); a bicarbonate; and a triptanwherein the dosage form is an oral dosage form having a shorter T_(max)of meloxicam than a reference dosage form that: 1) contains the sameamount of meloxicam, 2) does not contain an SBEβCD, and 3) does notcontain a bicarbonate.

Some embodiments include an inclusion complex of a triptan such asrizatriptan or frovatriptan in a cyclodextrin.

Some embodiments include a dosage form comprising: 1) an inclusioncomplex of a triptan, such as rizatriptan or frovatriptan, and acyclodextrin, or 2) a triptan, such as rizatriptan or frovatriptan, anda carbonate or a bicarbonate.

Some methods include administration of a product that contains acombination of a triptan with: 1) a cyclodextrin and/or 2) a bufferingagent. In some embodiments, the method involves treating a patient witha pharmaceutical formulation comprising a triptan, such as rizatriptanor frovatriptan, and a cyclodextrin and/or a carbonate/bicarbonate. Someembodiments may also include increasing the bioavailability of atriptan, such as rizatriptan or frovatriptan, or increasing the rate atwhich the triptan becomes bioavailable in a subject in need thereof ascompared to a formulation without a cyclodextrin orcarbonate/bicarbonate.

Some embodiments include a method of improving the pharmacokinetics of atriptan or an NSAID, comprising orally administering a dosage formdescribed herein to a mammal or human being in need of treatment withthe triptan or the NSAID.

Some embodiments include a method of treating pain, comprising orallyadministering a dosage form described herein to a mammal or human beingin need thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a depiction of the results described in Example 2 andcontained in Table 6.

FIG. 2 is another depiction of the results described in Example 2 andcontained in Table 6.

FIG. 3 is another depiction of the results described in Example 2 andcontained in Table 6.

FIG. 4 is another depiction of the results described in Example 2 andcontained in Table 6.

FIG. 5 is another depiction of the results described in Example 2 andcontained in Table 6.

FIG. 6 is another depiction of the results described in Example 2 andcontained in Table 6.

FIG. 7 is another depiction of the results described in Example 2 andcontained in Table 6.

FIG. 8 is another depiction of the results described in Example 2 andcontained in Table 6.

FIG. 9 is another depiction of the results described in Example 2 andcontained in Table 6.

FIG. 10 is another depiction of the results described in Example 2 andcontained in Table 6.

FIG. 11 is a plot of meloxicam plasma concentration at various timepoints over the first 24 hours for an embodiment of a dosage formdescribed herein and a commercially available meloxicam dosage form.

DETAILED DESCRIPTION

Meloxicam and some other NSAIDs, and other drugs, have poor aqueoussolubility which may reduce bioavailability and slow the onset of painrelief. One method of increasing the solubility and bioavailability ofmeloxicam or another drug is through the use of cyclodextrins incombination with meloxicam.

Generally, this may be accomplished using a dosage form, such as an oraldosage form, containing a triptan (such as rizatriptan), optionally incombination with an NSAID (such as meloxicam), and 1) a cyclodextrin(optionally in an inclusion complex), and/or 2) a buffering agent, suchas a bicarbonate. Administering this type of dosage form to a patientmay increase the bioavailability of the triptan (e.g. rizatriptan) orthe NSAID (e.g. meloxicam) in the patient or increase the rate at whichthe triptan (e.g. rizatriptan) or the NSAID (e.g. meloxicam) becomesbioavailable, or increase the rate at which the plasma concentration ofthe triptan or the NSAID increases. For example, the triptan or theNSAID may have a shorter T_(max), or may have an increased C_(max) orarea under the plasma concentration curve (AUC) as a result of theadministration of this type of dosage form.

Any suitable triptan may be used, such as sumatriptan, rizatriptan,naratriptan, eletriptan, donitriptan, almotriptan, frovatriptan,alvitriptan, zolmatriptan, etc., including combinations or saltsthereof. In some embodiments, the triptan comprises rizatriptan, whichhas the structure as shown below.

The NSAID may include, but is not limited to, celecoxib, rofecoxib,lumiracoxib, valdecoxib, parecoxib, etoricoxib, CS-502, JTE-522,L-745,337, NS398, aspirin, acetaminophen (considered to be an NSAID forthe purposes of the present disclosure), ibuprofen, flurbiprofen,ketoprofen, naproxen, oxaprozin, etodolac, indomethacin, ketorolac,lornoxicam, meloxicam, piroxicam, droxicam, tenoxicam, nabumetone,diclofenac, meclofenamate, mefenamic acid, diflunisal, sulindac,tolmetin, fenoprofen, suprofen, benoxaprofen, aceclofenac, tolfenamicacid, oxyphenbutazone, azapropazone, phenylbutazone, or combinationsthereof.

In some embodiments, the NSAID is meloxicam, which has the structure:

Meloxicam exhibits anti-inflammatory, analgesic, and antipyreticactivities. The meloxicam mechanism of action may be related to theinhibition of prostaglandin synthetase (cyclo-oxygenase, COX) which isinvolved in the initial steps of the arachidonic acid cascade, resultingin the reduced formation of prostaglandins, thromboxanes andprostacyclin.

A dosage form may be given enterally including, but not limited to,oral, sublingual, or rectal delivery, or parenterally including, but notlimited to, intravenous, intramuscular, intranasal, or subcutaneousdelivery.

The term “treating” or “treatment” broadly includes any kind oftreatment activity, including the diagnosis, cure, mitigation, orprevention of disease in man or other animals, or any activity thatotherwise affects the structure or any function of the body of man orother animals.

The dosage form may be used to treat, or provide relief of, any type ofpain including, but not limited to, migraine and other types ofheadache, inflammatory pain, musculoskeletal pain, neuropathic pain,chronic pain, acute pain, localized pain, systemic pain, cancer-relatedpain, acute pain, pain due to injury, pain due to illness (e.g., fever),post-operative pain, etc. In some instances, pain relief may bepalliative, or pain relief may be provided independent of improvement ofthe disease or condition or the underlying cause of the disease orcondition. For example, although the underlying disease may not improve,or may continue to progress, an individual suffering from the diseasemay experience pain relief. In some embodiments, the pain affects amuscle, nerve, cartilage, bone, ligament, tendon, tendon sheaths,bursae, or joint.

Migraine is a headache disorder characterized by recurrent headachesthat may be moderate to severe. The headaches may affect one half of thehead, may be pulsating in nature, and may last from 2 to 72 hours.Associated symptoms may include nausea, vomiting, and sensitivity tolight (photophobia), sound (phonophobia), or smell. The pain can be madeworse by physical activity. Migraines may be associated with an aura,which may be a short period of visual disturbance which signals that theheadache will soon occur.

In some methods, the dosage form may be administered to relieveinflammatory pain, including inflammatory musculoskeletal pain, pain dueto injury, arthritis pain, and complex regional pain syndrome. In otherembodiments, the inflammatory pain may be chronic or acute.

In some embodiments, the dosage form (e.g. a dosage form containing atriptan such as rizatriptan or frovatriptan, and/or an NSAID such asmeloxicam) may be administered to relieve arthritis pain, or other signsand/or symptoms of arthritis. Arthritis refers to inflammatory jointdiseases that can be associated with pain. Examples of arthritisinclude, but are not limited to, rheumatoid arthritis, juvenilerheumatoid arthritis (pauciarticular and polyarticular course),osteoarthritis, erosive osteoarthritis, sero-negative (non-rheumatoid),arthropathies, non-articular rheumatism, peri-articular disorders, axialspondyloarthritis, transient osteoarthritis of the hip, vertebral crushfractures, arthritis associated with osteoporosis, and neuropathicarthropathies including Charcot's foot, axial spondyloarthritisincluding ankylosing spondylitis, and SAPHO syndrome. In otherembodiments, the arthritis pain may be chronic or acute. In someembodiments the dosage form may be administered to relief the signsand/or symptoms of an arthritis including but not limited toosteoarthritis.

In some embodiments, the dosage form (e.g. a dosage form containing atriptan such as rizatriptan or frovatriptan, and/or an NSAID such asmeloxicam) may be administered to relieve neuropathic pain, includingdiabetic peripheral neuropathy, post-herpetic neuralgia, trigeminalneuralgia, monoradiculopathies, phantom limb pain, sciatica, pudendalneuralgia, and central pain. Other causes of neuropathic pain mayinclude, but are not limited to, cancer-related pain, lumbar nerve rootcompression, spinal cord injury, post-stroke pain, central multiplesclerosis pain, HIV-associated neuropathy, and radio-therapy orchemo-therapy associated neuropathy. The neuropathic pain may be chronicor acute.

For some methods, the dosage form (e.g. a dosage form containing atriptan such as rizatriptan or frovatriptan, and/or an NSAID such asmeloxicam) may be administered to relieve musculoskeletal pain. Examplesof musculoskeletal pain may include, but are not limited to, back pain,low back pain (e.g., lumbosacral pain), neck pain, infection, cramps,tendonitis, epicondylitis, carpal tunnel syndrome, joint pain,fibromyalgia, pain due to injury, Tunnel syndromes, pain associated withbone fractures, sprains, fibrous dysplasia, osteogenesis imperfecta,Paget's disease of bone, transient osteoporosis, and transientosteoporosis of the hip. In other embodiments, the musculoskeletal painmay be chronic or acute.

For some methods, administration of the dosage form (e.g. a dosage formcontaining a triptan such as rizatriptan or frovatriptan, and/or anNSAID such as meloxicam) may achieve a reduction in pain that lasts atleast about one hour, at least about two hours, at least about threehours, at least about four hours, at least about six hours, at leastabout eight hours, about 8 to about 24 hours, or about 24 hours. Inother embodiments, administration of the dosage form may achieve areduction in pain that is observed at about 10 minutes, at about 30minutes, at about one hour, at about two hours, at about three hours, atabout four hours, at about five hours, at about six hours, at or lessthan about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, or 60 minutes, at twohours or less, at three hours or less, or other time period bound bythese ranges, after administration of the dosage form.

A human being that is treated for a disease or condition with any of thedosage forms described herein (e.g. a dosage form containing a triptansuch as rizatriptan or frovatriptan, and/or an NSAID such as meloxicam)may be of any age. For example the person may have an age of about 10-90years, about 20-80 years, about 30-75 years, about 40-70 years, about1-16 years, about 80-95 years, about 18 years or more, about 20 years ormore, about 25 years or more, about 30 years or more, about 40 years ormore, about 45 years or more, about 50 years or more, about 55 years ormore, about 60 years or more, about 65 years or more, or any other agein a range bounded by, or between, any of these values.

In some embodiments, a human being that is treated for a disease orcondition with a dosage form (e.g. a dosage form containing a triptansuch as rizatriptan or frovatriptan, and/or an NSAID such as meloxicam)has suffered from the pain or condition associated with the pain for atleast 1 day, at least one week, at least 2 weeks, at least 1 month, atleast 6 weeks, at least 2 months, at least 3 months, at least 6 months,at least 1 year, at least 5 years, at least 10 years, at least 15 years,at least 20 years, at least 30 years, at least 40 years, at least 50years or any duration in a range bounded by, or between, any of thesevalues.

A cyclodextrin used in a dosage form with a drug (including meloxicam oranother NSAID, rizatriptan, frovatriptan, or another triptan) couldinclude a cyclodextrin, a cyclodextrin derivative, and/or a saltthereof. Cyclodextrins (also known as cycloamyloses) are generallycyclic polysaccharides which form a bucket-like shape. Cyclodextrinshelp to increase bioavailability of other molecules becausecyclodextrins are hydrophobic on the inside and hydrophilic on theoutside which helps to facilitate the transport of hydrophobic moleculesto a hydrophilic medium. The naturally occurring cyclodextrins includesix, seven, and eight glucose units (α, β, and γ-cyclodextrin,respectively). However, synthetic cyclodextrins containing more or lessglucose units are possible. In aqueous solutions, cyclodextrins can formcomplexes (i.e., an inclusion complex) with drugs by incorporating thedrug into the center/hydrophobic portion of the cyclodextrin ring;although cyclodextrins are also known to aggregate around a drug in amicelle-type structure. This ability of cyclodextrins may allow them toact as carriers of less soluble drugs to increase the drugs'bioavailability.

An inclusion complex of drug (including meloxicam or another NSAID,rizatriptan, frovatriptan, or another triptan) and cyclodextrin may bemore water-soluble relative to the non-complexed drug. The cyclodextrinmay be a naturally-occurring cyclodextrin (e.g., α, β, orγ-cyclodextrins) or a synthetic cyclodextrin. In some embodiments,α-cyclodextrins, derivatives, or salts thereof may be used.α-Cyclodextrins may include, but are not limited to,(2,3,6-tri-O-acetyl)-α-cyclodextrin,(2,3,6-tri-O-methyl)-α-cyclodextrin, (2,3,6-tri-O-octyl)-α-cyclodextrin,6-bromo-6-deoxy-α-cyclodextrin, 6-iodo-6-deoxy-α-cyclodextrin,(6-O-tertbutyl-dimethylsilyl)-α-cyclodextrin, butyl-α-cyclodextrin,succinyl-α-cyclodextrin, (2-hydroxypropyl)-α-cyclodextrin, orcombinations thereof.

In some embodiments, β-cyclodextrins, derivatives, or salts thereof maybe used. β-cyclodextrins may include, but are not limited to,hydroxypropyl-β-cyclodextrin, 6-monodeoxy-6-monoamino-β-cyclodextrin,glucosyl-β-cyclodextrin, maltosyl-β-cyclodextrin,6-O-α-D-glucosyl-β-cyclodextrin, 6-O-α-maltosyl-β-cyclodextrin,6-azido-6-deoxy-β-cyclodextrin,(2,3-di-O-acetyl-6-O-sulfo)-β-cyclodextrin, methyl-β-cyclodextrin,dimethyl-β-cyclodextrin (DMβCD), trimethyl-β-cyclodextrin (TMβCD),(2,3-di-O-methyl-6-O-sulfo)-β-cyclodextrin,(2,6-di-O-methyl)-β-cyclodextrin, (2,6-di-O-ethyl)-β-cyclodextrin,(2,3,6-tri-O-methyl)-β-cyclodextrin,(2,3,6-tri-O-acetyl)-β-cyclodextrin,-(2,3,6-tri-O-benzoyl)-β-cyclodextrin,(2,3,6-tri-O-ethyl)-β-cyclodextrin, 6-iodo-6-deoxy-β-cyclodextrin,6-(dimethyl-tert-butylsilyl)-6-deoxy-β-cyclodextrin,6-bromo-6-deoxy-β-cyclodextrin, monoacetyl-β-cyclodextrin,diacetyl-β-cyclodextrin, triacetyl-β-cyclodextrin,(3-O-acetyl-2,6-di-O-methyl)-β-cyclodextrin,(6-O-maltosyl)-β-cyclodextrin, (6-O-sulfo)-β-cyclodextrin,(6-O-t-butyldimethylsilyl-2,3-di-O-acetyl)-β-cyclodextrin,succinyl-(2-hydroxypropyl)-β-cyclodextrin,(2,6-di-O-)ethyl-β-cyclodextrin, (2-carboxyethyl)-β-cyclodextrin(CMEβCD), hydroxyethyl-β-cyclodextrin (HEβCD),(2-hydroxypropyl)-β-cyclodextrin, (2-hydroxypropyl)-β-cyclodextrin(HPβCD), (3-hydroxypropyl)-β-cyclodextrin (3HPβCD),(2,3-hydroxypropyl)-β-cyclodextrin (DHPβCD), butyl-3-cyclodextrin,methyl-β-cyclodextrin,silyl((6-O-tert-butyldimethyl)-2,3,-di-0-acetyl)-β-cyclodextrin,succinyl-β-cyclodextrin, (2-hydroxyisobutyl)-β-cyclodextrin, randomlymethylated-β-cyclodextrin, branched-β-cyclodextrin, or combinationsthereof.

In other embodiments, a β-cyclodextrin may be a sulfoalkyl ethercyclodextrin, derivative, or salt thereof. Examples of sulfoalkyl ethercyclodextrin derivatives may include, but are not limited to, sulfobutylether-β-cyclodextrin (e.g., SBEβCD, betadex, CAPTISOL®). In someembodiments, a SBEβCD may have about 4-8, about 5-8, about 4-7, about6-7, or about 6.5 sulfobutyl ether groups per cyclodextrin molecule.

In some embodiments, γ-cyclodextrins, derivatives, or salts thereof maybe used. γ-cyclodextrins may include carboxymethyl-γ-cyclodextrin,(2,3,6-tri-O-acetyl)-γ-cyclodextrin,(2,3,6-tri-O-methyl)-γ-cyclodextrin, (2,6-di-O-pentyl)-γ-cyclodextrin,6-(dimethyl-tert-butylsilyl)-6-deoxy-γ-cyclodextrin,6-bromo-6-deoxy-γ-cyclodextrin, 6-iodo-6-deoxy-γ-cyclodextrin,(6-O-t-butyldimethylsilyl)-γ-cyclodextrin, succinyl-γ-cyclodextrin,hydroxypropyl-γ-cyclodextrin, (2-hydroxypropyl)-γ-cyclodextrin,acetyl-γ-cyclodextrin, butyl-γ-cyclodextrin, or combinations thereof.

In some embodiments, the dosage form may include a bicarbonate, such assodium bicarbonate, potassium bicarbonate, etc. A bicarbonate may helpto increase the pharmacokinetics or bioavailability of meloxicam oranother drug, such as rizatriptan.

In some embodiments, enhanced bioavailability of a drug, such asmeloxicam or a triptan (e.g. rizatriptan) in the dosage form may beachieved by administering a dosage form comprising a salt form of thedrug, by generating an inclusion complex of the drug with cyclodextrin,and/or by including a bicarbonate. This may allow a reduced molar amountof the drug to be used as compared to other dosage forms containing thedrug in treating diseases or disorders.

Unless otherwise indicated, any reference to a compound herein, such asmeloxicam, an NSAID, a triptan, rizatriptan, or a cyclodextrin, bystructure, name, or any other means, includes pharmaceuticallyacceptable salts, alternate solid forms, such as polymorphs, solvates,hydrates, enantiomers, tautomers, deuterium-modified forms, or any otherchemical species, such as precursors, prodrugs, or any other chemicalspecies that may rapidly convert to a compound described herein underconditions in which the compounds are used as described herein.

In some embodiments, use of a cyclodextrin or a bicarbonate may improvethe oral bioavailability (e.g. a higher C_(max) and/or higher AUC) ofmeloxicam in a subject (human or animal) by at least about 10%, at leastabout 20%, at least about 30%, at least about 40%, at least about 50%,at least about 60%, at least about 70%, at least about 80%, at leastabout 90%, up to about 100%, up to about 200%, or any amount in a rangebounded by, or between, any of these values as compared toadministration of meloxicam alone.

In some embodiments, use of a cyclodextrin or a bicarbonate may improvethe oral bioavailability (e.g. a higher C_(max) and/or higher AUC) of atriptan such as rizatriptan or frovatriptan in subject (human or animal)by at least about 10%, at least about 20%, at least about 30%, at leastabout 40%, at least about 50%, at least about 60%, at least about 70%,at least about 80%, at least about 90%, up to about 100%, up to about200%, or any amount in a range bounded by, or between, any of thesevalues as compared to administration of the triptan alone.

Due to the improved bioavailability as described above, the dosage formmay contain, or a subject may receive, on a molar basis, less of thedrug, such as a triptan (e.g. rizatriptan or frovatriptan) or an NSAID(e.g. meloxicam) than would otherwise be administered of the drug alone.For example, a dosage form may contain, or a mammal may receive, atleast about 10 mole % less, at least about 20 mole % less, at leastabout 30 mole % less, at least about 40 mole % less, at least about 50mole % less, at least about 60 mole % less, at least about 70 mole %less, at least about 80 mole % less, at least about 85 mole % less,and/or up to about 90 mole % less, 95 mole % less, 98 mole % less, orany amount in a range bounded by, or between, any of these values ofmeloxicam as that would otherwise be administered of meloxicam alone.

In other embodiments, use of other NSAIDs, opioids, or other painmedications may be reduced by at least about 5%, at least about 10%, atleast about 15%, at least about 20%, at least about 25%, at least about30%, at least about 35%, at least about 40%, at least about 45%, atleast about 50%, at least about 60%, at least about 70%, at least about80%, or at least about 90%, up to about 100%, or any amount in a rangebounded by, or between, any of these values when administered with adrug such as an triptan (e.g. rizatriptan) or an NSAID (e.g. meloxicam),with a cyclodextrin and/or a bicarbonate, as compared to administrationof the NSAID, the opioid or the other pain medication alone.

In some embodiments, a dosage form may contain an NSAID, such ascelecoxib, rofecoxib, lumiracoxib, valdecoxib, parecoxib, etoricoxib,CS-502, JTE-522, L-745,337, NS398, aspirin, acetaminophen (considered tobe an NSAID for the purposes of the present disclosure), ibuprofen,flurbiprofen, ketoprofen, naproxen, oxaprozin, etodolac, indomethacin,ketorolac, lornoxicam, piroxicam, droxicam, tenoxicam, nabumetone,diclofenac, meclofenamate, mefenamic acid, diflunisal, sulindac,tolmetin, fenoprofen, suprofen, benoxaprofen, aceclofenac, tolfenamicacid, oxyphenbutazone, azapropazone, phenylbutazone, in an amount ofabout 1-1000 mg, about 1-500 mg, about 1-400 mg, about 1-300 mg, about1-200 mg, about 1-100 mg, about 1-50 mg, about 1-10 mg, about 1-5 mg,about 2-6 mg, about 3-7 mg, about 4-8 mg, about 5-10 mg, about 7-12 mg,about 5-15 mg, about 10-20 mg, about 15-25 mg, about 20-30 mg, about25-35 mg, about 30-40 mg, about 35-45 mg, about 40-50 mg, about 50-150mg, about 50-100 mg, about 100-200 mg, about 150-250 mg, about 200-300mg, about 250-350 mg, about 300-400 mg, about 350-450 mg, about 400-500mg, about 100 mg, about 200 mg, about 325 mg, or any amount in a rangebounded by, or between, any of these values. These doses may be a safedose for repeated administration, such as 1, 2, 3, or 4 times a day, orrepeated at an interval of 2 days, 3 days, 4 days, 5 days, 6 days, 7days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31days, about 1 week, about 4 weeks, about 6 weeks, about 1-2 months,about 6 weeks, about 2-3 months, about 3-4 months, about 4-5 months,about 5-6 months, about 6-7 months, about 7-8 months, about 8-9 months,about 9-10 months, about 10-11 months, about 11-12 months, about 2years, etc.

In some embodiments, a dosage form may contain meloxicam in an amount ofabout 1-50 mg; about 1-10 mg; about 1-5 mg; about 10-40 mg; about 1-35mg; about 2-6 mg, about 3-7 mg, about 4-8 mg, about 5-10 mg, about 7-12mg, about 5-15 mg, about 10-20 mg, about 10-30 mg, about 18-22 mg, about19-21 mg, about 15-25 mg, about 20-30 mg, about 25-35 mg, about 30-40mg, about 35-45 mg, about 40-50 mg, about 1-25 mg; about 1-15 mg; about5-20 mg; about 5 mg; about 7.5 mg; about 10 mg; about 15 mg; about 20mg; about 30 mg; or any amount in a range bounded by, or between, any ofthese values. For any amounts of meloxicam (or any other compound)described herein, salt forms of meloxicam (or another compound) may bepresent in the amounts recited above, or amounts that are molarequivalents to these amounts for the non-salt form of meloxicam (oranother compound). These doses may be a safe dose for repeatedadministration, such as 1, 2, 3, or 4 times a day, or repeated at aninterval of 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, about 1-2months, about 4 weeks, about 6 weeks, about 2-3 months, about 3-4months, about 4-5 months, about 5-6 months, about 6-7 months, about 7-8months, about 8-9 months, about 9-10 months, about 10-11 months, about11-12 months, about 2 years, etc.

For some dosage forms, a drug (such as meloxicam, frovatriptan, orrizatriptan) forms a complex with the substituted-β-cyclodextrin orother cyclodextrin which may be formulated into a solid dosage form.Such a dosage form may be suitable for oral administration. Adrug-cyclodextrin inclusion complex may also be dissolved in water oranother solvent to form a parenteral formulation. However, physicalmixtures of drug and the substituted-β-cyclodextrin or othercyclodextrins that are not inclusion complexes may also be used in oralor parenteral dosage forms.

Formation of an inclusion complex of a drug (such as meloxicam,frovatriptan, or rizatriptan) and a cyclodextrin may help to improve theproperties of a dosage form. For some inclusion complexes, the drug andthe cyclodextrin (e.g., SBEβCD) may have a molar ratio of about 0.5-2 (amolar ratio of 0.5 is 0.5 moles of the drug to 1 mole of cyclodextrin),about 0.5-0.7, about 0.6-0.8, about 0.7-0.9, about 0.8-1, about 0.9-1.1,about 1-1.2, about 1.1-1.3, about 1.2-1.4, about 1.3-1.5, about 1.4-1.6,about 1.5-1.7, about 1.6-1.8, about 1.7-1.9, about 1.8-2, about 1.9-2.1,about 2-2.2, about 0.8-1.2, about 1, or any ratio in a range bounded byany of these values.

In some embodiments, an inclusion complex is formed by (1) mixing ahomogeneous solution of a drug such as meloxicam or a triptan with ahomogeneous solution of the cyclodextrin to form a homogeneous solutionof the drug and the cyclodextrin, and (2) removing or evaporating thesolvent of the homogeneous solution of the drug and the cyclodextrin toform the complex comprising the inclusion complex of the drug in acyclodextrin. In some embodiments, the solutions can be pH-adjustedaqueous solutions. The pH can be adjusted using a buffering agent. Insome embodiments, the solvent can be removed or evaporated bylyophilization, spray drying, or any other means that is suitable. Insome embodiments, the solvent can be removed by vacuum drying, etc.

For some dosage forms, a cyclodextrin (e.g., SBEβCD) may be employed ina weight ratio to the meloxicam within the range of about 1-1000 (e.g. 1g of cyclodextrin per 1 g of meloxicam is a weight ratio of 1); about1-500, about 1-5, about 1-20; about 1-10; about 1-15; about 2-4, about3-5, about 4-6, about 5-7, about 6-8, about 7-9, about 8-10, about0.01-1; about 0.05-1; about 0.1-1; about 0.2-1; about 0.3-1, about0.4-1, about 0.5-1, about 0.6-1, about 0.7-1, about 0.8-1, or any weightratio in a range bounded by, or between, any of these values. Each typeof cyclodextrin employed may have a different weight ratio to themeloxicam in the dosage form.

For some dosage forms, a cyclodextrin (e.g., SBEβCD) may be employed ina weight ratio to the triptan, e.g. rizatriptan or frovatriptan, withinthe range of about 1-1000 (e.g. 10 g of cyclodextrin per 1 g ofrizatriptan or frovatriptan is a weight ratio of 10); about 1-500; about1-100; about 1-50; about 1-20; about 1-10; about 1-15; about 1-5, about2-4, about 3-5, about 4-6, about 5-7, about 6-8, about 7-9, about 8-10,about 0.01-1; about 0.05-1; about 0.1-1; about 0.2-1; about 0.3-1; about0.4-1; about 0.5-1; about 0.6-1; about 0.7-1; about 0.8-1; or any weightratio in a range bounded by, or between, any of these values. Each typeof cyclodextrin employed may have a different weight ratio to thetriptan in the dosage form.

For some dosage forms, a cyclodextrin (e.g., SBEβCD) may be employed ina weight ratio to rizatriptan within the range of about 1-1000 (e.g. 10g of cyclodextrin per 1 g of rizatriptan is a weight ratio of 10); about1-500; about 1-100; about 1-50; about 1-20; about 1-10; about 1-15;about 2-4, about 3-5, about 4-6, about 5-7, about 6-8, about 7-9, about8-10, about 9-11, about 10-12, about 11-13, about 12-14, about 13-15,about 14-16, about 15-17, about 16-18, about 17-19, about 18-20, about19-21, about 0.001-1; about 0.01-1; about 0.05-1; about 0.1-1; about0.2-1; about 0.3-1, about 0.4-1, about 0.5-1, about 0.6-1, about 0.7-1,about 0.8-1, or any weight ratio in a range bounded by, or between, anyof these values. Each type of cyclodextrin employed may have a differentweight ratio to rizatriptan in the dosage form.

In some embodiments; a dosage form may contain rizatriptan in an amountof about 1-50 mg; about 1-10 mg; about 20-30 mg; about 30-40 mg; orabout 40-50 mg; about 10-40 mg; about 1-35 mg; about 1-25 mg; about 1-15mg; about 1-10 mg; about 5-20 mg; about 1-50 mg; about 1-5 mg; about 2-6mg; about 3-7 mg; about 4-8 mg; about 5-10 mg; about 6-11 mg; about 7-12mg; about 8-13 mg; about 9-11 mg; about 9-14 mg; about 10-15 mg; about11-16 mg; about 12-17 mg; about 13-18 mg; about 14-19 mg; about 15-20mg; about 5-15 mg; about 10-20 mg; about 20-30 mg; about 30-40 mg; about40-50 mg; about 0.5 mg; about 1 mg; about 1.5 mg; about 2 mg; about 2.5mg; about 3 mg; about 3.5 mg; about 4 mg; about 4.5 mg; about 5 mg;about 6 mg; about 7 mg; about 7.5 mg; about 10 mg; about 15 mg; about 30mg; or any amount in a range bounded by, or between, any of thesevalues.

For any amounts of rizatriptan described herein, salt forms ofrizatriptan may be present in the amounts recited above, or amounts thatare molar equivalents to these amounts for the rizatriptan free base.For example, assuming that the molecular weight of rizatriptan free baseis 269.3 g/mol, 10 mg of rizatriptan is 37.1 mmol of rizatriptan. Thus,a molar equivalent of 10 mg of rizatriptan free base would be the massof 37.1 mmol of that salt form. For example, for the benzoate salt(mw=391.2 g/mol), the molar equivalent of 10 mg of the free base (or37.1 mmol), would be 14.5 mg. These doses may be a safe dose forrepeated administration, such as 1, 2, 3, or 4 times a day, or repeatedat an interval of 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 4weeks, 4-6 weeks, about 1-2 months, about 6 weeks, about 2-3 months,about 3-4 months, about 4-5 months, about 5-6 months, about 6-7 months,about 7-8 months, about 8-9 months, about 9-10 months, about 10-11months, about 11-12 months, etc.

The other triptans may be administered to patients at any dosageseffective at relieving pain. In some embodiments, the dosage form maycontain the triptan in any amount in a range bounded by any of thevalues described above.

In some embodiments, a dosage form may contain frovatriptan or anothertriptan in an amount of about 1-50 mg; about 1-10 mg; about 20-30 mg;about 30-40 mg; or about 40-50 mg; about 10-40 mg; about 1-35 mg; about1-25 mg; about 1-15 mg; about 5-20 mg; about 1-5 mg; about 2-6 mg; about3-7 mg; about 4-8 mg; about 5-10 mg; about 6-11 mg; about 7-12 mg; about8-13 mg; about 9-11 mg; about 9-14 mg; about 10-15 mg; about 11-16 mg;about 12-17 mg; about 13-18 mg; about 14-19 mg; about 15-20 mg; about5-15 mg; about 10-20 mg; about 0.5 mg; about 1 mg; about 1.5 mg; about 2mg; about 2.5 mg; about 3 mg; about 3.5 mg; about 4 mg; about 4.5 mg;about 5 mg; about 6 mg; about 7 mg; about 7.5 mg; about 10 mg; about 15mg; about 30 mg; or any amount in a range bounded by, or between, any ofthese values. These doses may be a safe dose for repeatedadministration, such as 1, 2, 3, or 4 times a day, or repeated at aninterval of 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, about 4weeks, about 4-6 weeks, about 1-2 months, about 6 weeks, about 2-3months, about 3-4 months, about 4-5 months, about 5-6 months, about 6-7months, about 7-8 months, about 8-9 months, about 9-10 months, about10-11 months, about 11-12 months, about 2 years, etc.

For some dosage forms, the cyclodextrin (such as SBEβCD) may be presentin an amount of about 1-200 mg; about 1-100 mg; 25-175 mg; about 50-150mg; about 50-100 mg; about 50-200 mg; about 25-100 mg; about 75-150 mg;about 100-175 mg; about 20-80 mg; about 25-50 mg; about 60-100 mg; about80-100 mg; about 100 mg; about 80-120 mg; about 100-120 mg; about100-140 mg; about 120-160 mg; about 140-180 mg; about 150-200 mg, about100-150 mg; about 30-90 mg; about 40-60 mg; about 40-80 mg; about 50-70mg, about 55-65 mg, about 60-62 mg, or any amount in a range bounded by,or between, any of these values.

For some dosage forms, an inclusion complex of a drug (such as meloxicamor another NSAID, or rizatriptan, frovatriptan or another triptan) andcyclodextrin is about 1-10%, 5-20%, 5-15%, 6-16%, 7-17%, 8-18%, 9-19%,10-20%, 15-30%, 30-40%, 40-50%, 50-70%, or 70-90% of the total weight ofthe dosage form, or any percentage in a range bounded by any of thesevalues.

Some dosage forms contain a bicarbonate (e.g., sodium bicarbonate) inamount of about 1-2000 mg; about 1-1000 mg; about 100-1000 mg; about200-800 mg; about 1-500 mg; about 1-200 mg; about 1-100 mg; about 50-750mg; about 5004000 mg; about 100-500 mg; about 100-300 mg; about 500-1000mg; about 300-700 mg; about 400-600 mg; about 50-250 mg; about 50-100mg; about 250-750 mg; about 100-200 mg; about 200-300 mg; about 300-400mg; about 400-500 mg; about 410-510 mg; about 420-520 mg; about 430-530mg; about 440-540 mg; about 450-550 mg; about 460-560 mg; about 470-570mg; about 480-580 mg; about 490-590 mg; about 500-600 mg; about 600-700mg; about 700-800 mg; about 800-900 mg; about 900-1000 mg; about 150-650mg; about 350-850 mg; about 400 mg; about 450 mg; about 500 mg, about550 mg; about 600 mg; or any amount in a range bounded by, or between,any of these values.

A bicarbonate, such as sodium bicarbonate, may be at least about 10%, atleast about 15%, at least about 20%, about 20-40%, about 30-50%, about40-60%, about 50-70%, about 60-80%, or about 70-90%, or any percentagein a range bounded by any of these values, of the total weight of thedosage form.

In some embodiments, the daily dose of meloxicam, or the amount ofmeloxicam administered in a single day (either in one administration, orby more than one divided doses adding up to the daily dose) is about 2-5mg, about 2-6 mg, about 2-7 mg, about 2-8 mg, about 2-9 mg, about 2-10mg, about 2-11 mg, about 2-12 mg, about 2-13 mg, about 2-14 mg, about2-15 mg, about 2-16 mg, about 2-17 mg, about 2-18 mg, about 2-19 mg,about 2-20 mg, about 2-21 mg, about 2-22 mg, about 2-23 mg, about 2-24mg, about 2-25 mg, about 2-26 mg, about 2-27 mg, about 2-28 mg, about2-29 mg, about 2-30 mg, about 2-35 mg, about 2-40 mg, about 2-45 mg,about 2-50 mg, about 2-55 mg, about 2-60 mg, about 2-65 mg, about 2-70mg, about 2-75 mg, about 3-8 mg, about 4-9 mg, about 5-10 mg, about 6-11mg, about 7-12 mg, about 8-13 mg, about 9-14 mg, about 10-15 mg, about11-16 mg, about 12-17 mg, about 13-18 mg, about 14-19 mg, about 15-20mg, about 16-21 mg, about 17-22 mg, about 18-23 mg, about 19-24 mg,about 20-25 mg, about 21-26 mg, about 22-27 mg, about 23-28 mg, about24-29 mg, about 25-30 mg, about 26-31 mg, about 27-32 mg, about 28-33mg, about 29-34 mg, about 30-35 mg, about 31-36 mg, about 32-37 mg,about 33-38 mg, about 34-39 mg, about 35-40 mg, about 36-41 mg, about37-42 mg, about 38-43 mg, about 39-44 mg, about 40-45 mg, about 41-46mg, about 42-47 mg, about 43-48 mg, about 44-49 mg, about 45-50 mg,about 46-51 mg, about 47-52 mg, about 48-53 mg, about 49-54 mg, about50-55 mg, about 51-56 mg, about 52-57 mg, about 53-58 mg, about 54-59mg, about 55-60 mg, about 56-61 mg, about 57-62 mg, about 58-63 mg,about 59-64 mg, about 60-65 mg, about 61-66 mg, about 62-67 mg, about63-68 mg, about 64-69 mg, about 65-70 mg, about 66-71 mg, about 67-72mg, about 68-73 mg, about 69-74 mg, about 70-75 mg, about 5-10 mg, about10-15 mg, about 15-20 mg, about 20-25 mg, about 25-30 mg, about 30-35mg, or any amount in a range bounded by any of these values. The dailydose may be given as a single dose, given once a day, or may be given in2, 3, 4, or more divided doses during a day.

In some embodiments, the weekly dose of meloxicam or the amount ofmeloxicam administered in a week (either in one administration, or bymore than one divided doses adding up to the weekly dose) is about1-1000 mg; about 1-500 mg; about 10-250 mg; about 100-300 mg; about10-100 mg; about 10450 mg; about 10-300 mg; about 20-150 mg; about 20-60mg; about 30-70 mg; about 40-60 mg; about 50-70 mg; about 70-90 mg;about 90-110 mg; about 80-450 mg; about 80-100 mg; about 90-110 mg;about 100-120 mg; about 110430 mg; about 120-140 mg; about 130-150 mg;about 140-160 mg; about 150-170 mg; about 160-180 mg; about 170490 mg;about 180-200 mg; about 190-210 mg; about 200-220 mg; about 210-230 mg;about 220-240 mg; about 230-250 mg; about 240-260 mg; about 250-270 mg;about 260-280 mg; about 270-290 mg; about 280-300 mg; about 290-310 mg;about 300-320 mg; about 310-330 mg; about 320-340 mg; about 330-350 mg;about 340-360 mg; about 350-370 mg; about 360-380 mg; about 370-390 mg;about 380-400 mg; about 390-410 rig; about 400-420 mg; about 410-430 mg;about 420-440 mg; about 430-450 mg; about 50 mg; about 55 mg; about100-150 mg; about 30-100 mg; or any amount in a range bounded by, orbetween, any of these values. The weekly dose may be given as a singledose, given once a week, or may be given in 2, 3, 4, 5, 6, or 7individual doses during a week.

In some embodiments, the monthly dose of meloxicam (e.g., an oral dose),or a dose administered over a period of a month, is about 5000 mg orless; about 4000 mg or less; about 3000 mg or less; about 2000 mg orless; about 1000 mg or less; about 700 mg or less; about 600 mg or less;about 300-2400 mg; about 300-350 mg; about 310-360 mg; about 320-370 mg;about 330-380 mg; about 340-390 mg; about 350-400 mg; about 360-410 mg;about 370-420 mg; about 380-430 mg; about 390-440 mg; about 400-450 mg;about 410-460 mg; about 420-470 mg; about 430-480 mg; about 440-490 mg;about 450-500 mg; about 460-510 mg; about 470-520 mg; about 480-530 mg;about 490-540 mg; about 500-550 mg; about 510-560 mg; about 520-570 mg;about 530-580 mg; about 540-590 mg; about 550-600 mg; about 560-610 mg;about 570-620 mg; about 580-630 mg; about 590-640 mg; about 600-650 mg;about 610-660 mg; about 620-670 mg; about 630-680 mg; about 640-690 mg;about 650-700 mg; about 660-710 mg; about 670-720 mg; about 680-730 mg;about 690-740 mg; about 700-750 mg; about 710-760 mg; about 720-770 mg;about 730-780 mg; about 740-790 mg; about 750-800 mg; about 760-810 mg;about 770-820 mg; about 780-830 mg; about 790-840 mg; about 800-850 mg;about 810-860 mg; about 820-870 mg; about 830-880 mg; about 840-890 mg;about 850-900 mg; about 860-910 mg; about 870-920 mg; about 880-930 mg;about 890-940 mg; about 900-950 mg; about 910-960 mg; about 920-970 mg;about 930-980 mg; about 940-990 mg; about 950-1000 mg; about 960-1010mg; about 970-1020 mg; about 980-1030 mg; about 990-1040 mg; about1000-1050 mg; about 1010-1060 mg; about 1020-1070 mg; about 1030-1080mg; about 1040-1090 mg; about 1050-1100 mg; about 1060-1110 mg; about1070-1120 mg; about 1080-1130 mg; about 1090-1140 mg; about 1100-1150mg; about 1110-1160 mg; about 1120-1170 mg; about 1130-1180 mg; about1140-1190 mg; about 1150-1200 mg; about 1160-1210 mg; about 1170-1220mg; about 1180-1230 mg; about 1190-1240 mg; about 1200-1250 mg; about1210-1260 mg; about 1220-1270 mg; about 1230-1280 mg; about 1240-1290mg; about 1250-1300 mg; about 1260-1310 mg; about 1270-1320 mg; about1280-1330 mg; about 1290-1340 mg; about 1300-1350 mg; about 1310-1360mg; about 1320-1370 mg; about 1330-1380 mg; about 1340-1390 mg; about1350-1400 mg; about 1360-1410 mg; about 1370-1420 mg; about 1380-1430mg; about 1390-1440 mg; about 1400-1450 mg; about 1410-1460 mg; about1420-1470 mg; about 1430-1480 mg; about 1440-1490 mg; about 1450-1500mg; about 1460-1510 mg; about 1470-1520 mg; about 1480-1530 mg; about1490-1540 mg; about 1500-1550 mg; about 1510-1560 mg; about 1520-1570mg; about 1530-1580 mg; about 1540-1590 mg; about 1550-1600 mg; about1560-1610 mg; about 1570-1620 mg; about 1580-1630 mg; about 1590-1640mg; about 1600-1650 mg; about 1610-1660 mg; about 1620-1670 mg; about1630-1680 mg; about 1640-1690 mg; about 1650-1700 mg; about 1660-1710mg; about 1670-1720 mg; about 1680-1730 mg; about 1690-1740 mg; about1700-1750 mg; about 1710-1760 mg; about 1720-1770 mg; about 1730-1780mg; about 1740-1790 mg; about 1750-1800 mg; about 1760-1810 mg; about1770-1820 mg; about 1780-1830 mg; about 1790-1840 mg; about 1800-1850mg; about 1810-1860 mg; about 1820-1870 mg; about 1830-1880 mg; about1840-1890 mg; about 1850-1900 mg; about 1860-1910 mg; about 1870-1920mg; about 1880-1930 mg; about 1890-1940 mg; about 1900-1950 mg; about1910-1960 mg; about 1920-1970 mg; about 1930-1980 mg; about 1940-1990mg; about 1950-2000 mg; about 1960-2010 mg; about 1970-2020 mg; about1980-2030 mg; about 1990-2040 mg; about 2000-2050 mg; about 2010-2060mg; about 2020-2070 mg; about 2030-2080 mg; about 2040-2090 mg; about2050-2100 mg; about 2060-2110 mg; about 2070-2120 mg; about 2080-2130mg; about 2090-2140 mg; about 2100-2150 mg; about 2110-2160 mg; about2120-2170 mg; about 2130-2180 mg; about 2140-2190 mg; about 2150-2200mg; about 2160-2210 mg; about 2170-2220 mg; about 2180-2230 mg; about2190-2240 mg; about 2200-2250 mg; about 2210-2260 mg; about 2220-2270mg; about 2230-2280 mg; about 2240-2290 mg; about 2250-2300 mg; about2260-2310 mg; about 2270-2320 mg; about 2280-2330 mg; about 2290-2340mg; about 2300-2350 mg; about 2310-2360 mg; about 2320-2370 mg; about2330-2380 mg; about 2340-2390 mg; about 2350-2400 mg; about 1-4000 mg;about 1-1000 mg; about 10-1000 mg; about 50-1000 mg; about 10-600 mg;about 40-600 mg; about 50-600 mg; about 40-400 mg; about 50-200 mg;about 200-240 mg; about 240-280 mg; about 280-320 mg; about 320-360 mg;about 360-400 mg; about 400-450 mg; about 450-500 mg; about 500-600 mg;about 250-350 mg; about 100-600 mg; about 40-2000 mg; about 40-800 mg;about 100-900 mg; about 100-800 mg; about 40-1000 mg; about 50-1000 mg;about 100-1000 mg; or any monthly dose in a range bounded by, orbetween, any of these values. A monthly dose may be given as a singledose, or as two or more individual doses administered during the month.In some embodiments, the monthly dose is administered bi-weekly in 2 or3 divided doses. In some embodiments, the monthly dose is administeredweekly in 4 or 5 divided doses. In some embodiments, the monthly dose isadministered daily in 28 to 31 divided doses, or in 56 to 62 divideddoses or more. In some embodiments, the monthly dose is administered in5 to 15 individual doses during the month. The monthly dose may beadministered for only 1 month, or may be repeatedly administered for 2,3, 4, 5, 6, or more months.

In some embodiments, the daily dose of frovatriptan or another triptan(e.g., an oral dose, a parenteral dose, etc.) is about 0.5-1 mg, about1-2 mg, about 2-3 mg, about 3-4 mg, about 2-5 mg, about 2-6 mg, about2-7 mg, about 2-8 mg, about 2-9 mg, about 2-10 mg, about 2-11 mg, about2-12 mg, about 2-13 mg, about 2-14 mg, about 2-15 mg, about 2-16 mg,about 2-17 mg, about 2-18 mg, about 2-19 mg, about 2-20 mg, about 2-21mg, about 2-22 mg, about 2-23 mg, about 2-24 mg, about 2-25 mg, about2-26 mg, about 2-27 mg, about 2-28 mg, about 2-29 mg, about 2-30 mg,about 2-35 mg, about 2-40 mg, about 5-10 mg, about 10-15 mg, about 15-20mg, about 20-25 mg, about 25-30 mg, about 30-35 mg, or any amount in arange bounded by any of these values.

In some embodiments, the daily dose of rizatriptan is about 0.5-100 mg,about 5-50 mg, about 1-10 mg, about 10-20 mg, about 20-30 mg, about30-40 mg, about 40-50 mg, about 1-5 mg, about 1-6 mg, about 2-7 mg,about 3-8 mg, about 4-9 mg, about 5-10 mg, about 6-11 mg, about 7-12 mg,about 8-13 mg, about 9-14 mg, about 10-15 mg, about 11-16 mg, about12-17 mg, about 13-18 mg, about 14-19 mg, about 15-20 mg, about 16-21mg, about 17-22 mg, about 18-23 mg, about 19-24 mg, about 20-25 mg,about 21-26 mg, about 22-27 mg, about 23-28 mg, about 24-29 mg, about25-30 mg, about 26-31 mg, about 27-32 mg, about 28-33 mg, about 29-34mg, about 30-35 mg, about 31-36 mg, about 32-37 mg, about 33-38 mg,about 34-39 mg, about 35-40 mg, about 36-41 mg, about 37-42 mg, about38-43 mg, about 39-44 mg, about 40-45 mg, about 41-46 mg, about 42-47mg, about 43-48 mg, about 44-49 mg, about 45-50 mg, about 46-51 mg,about 47-52 mg, the 48-53 mg, about 49-54 mg, about 50-55 mg, or anyamount in a range bounded by any of these values. The daily dose may begiven as a single dose, given once a day, or may be given in 2, 3, 4, ormore divided doses during a day.

In some embodiments, the weekly dose of frovatriptan or another triptan(e.g., an oral dose) is about 1-1000 mg; about 1-500 mg; about 10-250mg; about 100-300 mg; about 10-100 mg; about 10-150 mg; about 10-300 mg;about 20-150 mg; about 20-60 mg; about 30-70 mg; about 40-60 mg; about50-70 mg; about 70-90 mg; about 90-110 mg; about 50 mg; about 55 mg;about 100450 mg; about 30-100 mg; about 1-20 mg; about 1-10 mg; about2-10 mg; about 2-5 mg; about 540 mg; about 2.5 mg; about 5 mg; about 7.5mg; or any amount in a range bounded by, or between, any of thesevalues. The weekly dose may be given as a single dose, given once aweek, or may be given in 2, 3, 4, 5, 6, or 7 individual doses during aweek.

In some embodiments, the weekly dose of rizatriptan is about 1-1000 mg;about 10-400 mg, about 50-250 mg, about 1-500 mg; about 10-250 mg; about100-300 mg; about 10-100 mg; about 10-150 mg; about 10-300 mg; about20450 mg; about 20-60 mg; about 30-70 mg; about 40-60 mg; about 50-70mg; about 70-90 mg; about 90-110 mg; about 50 mg; about 55 mg; about100-150 mg; about 30-100 mg; about 1-20 mg; about 1-10 mg; about 2-10mg; about 2-5 mg; about 5-10 mg; about 1-50 mg; about 10-60 mg; about20-70 mg; about 30-80 mg; how about 40-90 mg; about 50-100 mg; about60410 mg; about 70-120 mg; about 80-130 mg; about 90-140 mg; about100450 mg; about 110-160 mg; about 120470 mg; about 130-180 rig; about140-190 mg; about 150-200 mg; about 160-210 mg; about 170-220 mg; about180-230 mg; about 190-240 mg; about 200-250 mg; about 210-260 mg; about220-270 mg; about 230-280 mg; about 240-290 mg; about 250-300 mg; about260-310 mg; about 270-320 mg; about 280-330 mg; about 290-340 mg; about300-350 mg; about 310-360 mg; about 320-370 mg; about 330-380 mg; about340-390 mg; about 350-400 mg; or any amount in a range bounded by, orbetween, any of these values. The weekly dose may be given as a singledose, given once a week, or may be given in 2, 3, 4, 5, 6, or 7individual doses during a week.

In some embodiments, the monthly dose of frovatriptan or another triptan(e.g., an oral dose), or a dose administered over a period of a month,is about 5000 mg or less; about 4000 mg or less; about 3000 mg or less;about 2000 mg or less; about 1000 mg or less; about 700 mg or less;about 600 mg or less; about 1-4000 mg; about 1-1000 mg; about 10-1000mg; about 50-1000 mg; about 10-600 mg; about 40-600 mg; about 50-600 mg;about 40-400 mg; about 50-200 mg; about 200-240 mg; about 240-280 mg;about 280-320 mg; about 320-360 mg; about 360-400 mg; about 400-450 mg;about 450-500 mg; about 500-600 mg; about 250-350 mg; about 100-600 mg;about 40-2000 mg; about 40-800 mg; about 100-900 mg; about 100-800 mg;about 40-1000 mg; about 50-1000 mg; about 100-1000 mg; about 10-80 mg;about 10-40 mg; about 20-30 mg; or any monthly dose in a range boundedby, or between, any of these values. A monthly dose may be given as asingle dose, or as two or more individual doses administered during themonth. In some embodiments, the monthly dose is administered bi-weeklyin 2 or 3 divided doses. In some embodiments, the monthly dose isadministered weekly in 4 or 5 divided doses. In some embodiments, themonthly dose is administered daily in 28 to 31 divided doses, or in 56to 62 divided doses or more. In some embodiments, the monthly dose isadministered in 5 to 15 individual doses during the month. The monthlydose may be administered for only 1 month, or may be repeatedlyadministered for 2, 3, 4, 5, 6, or more months.

In some embodiments, the monthly dose of rizatriptan, or a total doseadministered within a period of a month, is about 5000 mg or less; about4000 mg or less; about 3000 mg or less; about 2000 mg or less; about1000 mg or less; about 700 mg or less; about 600 mg or less; about1-4000 mg; about 1-1000 mg; about 10-1000 mg; about 50-1000 mg; about10-600 mg; about 40-600 mg; about 50-600 mg; about 150-2400 mg, about150-200 mg; about 160-210 mg; about 170-220 mg; about 180-230 mg; about190-240 mg; about 200-250 mg; about 210-260 mg; about 220-270 mg; about230-280 mg; about 240-290 mg; about 250-300 mg; about 260-310 mg; about270-320 mg; about 280-330 mg; about 290-340 mg; about 300-350 mg; about310-360 mg; about 320-370 mg; about 330-380 mg; about 340-390 mg; about350-400 mg; about 360-410 mg; about 370-420 mg; about 380-430 mg; about390-440 mg; about 400-450 mg; about 410-460 mg; about 420-470 mg; about430-480 mg; about 440-490 mg; about 450-500 mg; about 460-510 mg; about470-520 mg; about 480-530 mg; about 490-540 mg; about 500-550 mg; about510-560 mg; about 520-570 mg; about 530-580 mg; about 540-590 mg; about550-600 mg; about 560-610 mg; about 570-620 mg; about 580-630 mg; about590-640 mg; about 600-650 mg; about 610-660 mg; about 620-670 mg; about630-680 mg; about 640-690 mg; about 650-700 mg; about 660-710 mg; about670-720 mg; about 680-730 mg; about 690-740 mg; about 700-750 mg; about710-760 mg; about 720-770 mg; about 730-780 mg; about 740-790 mg; about750-800 mg; about 760-810 mg; about 770-820 mg; about 780-830 mg; about790-840 mg; about 800-850 mg; about 810-860 mg; about 820-870 mg; about830-880 mg; about 840-890 mg; about 850-900 mg; about 860-910 mg; about870-920 mg; about 880-930 mg; about 890-940 mg; about 900-950 mg; about910-960 mg; about 920-970 mg; about 930-980 mg; about 940-990 mg; about950-1000 mg; about 960-1010 mg; about 970-1020 mg; about 980-1030 mg;about 990-1040 mg; about 1000-1050 mg; about 1010-1060 mg; about1020-1070 mg; about 1030-1080 mg; about 1040-1090 mg; about 1050-1100mg; about 1060-1110 mg; about 1070-1120 mg; about 1080-1130 mg; about1090-1140 mg; about 1100-1150 mg; about 1110-1160 mg; about 1120-1170mg; about 1130-1180 mg; about 1140-1190 mg; about 1150-1200 mg; about1160-1210 mg; about 1170-1220 mg; about 1180-1230 mg; about 1190-1240mg; about 1200-1250 mg; about 1210-1260 mg; about 1220-1270 mg; about1230-1280 mg; about 1240-1290 mg; about 1250-1300 mg; about 1260-1310mg; about 1270-1320 mg; about 1280-1330 mg; about 1290-1340 mg; about1300-1350 mg; about 1310-1360 mg; about 1320-1370 mg; about 1330-1380mg; about 1340-1390 mg; about 1350-1400 mg; about 1360-1410 mg; about1370-1420 mg; about 1380-1430 mg; about 1390-1440 mg; about 1400-1450mg; about 1410-1460 mg; about 1420-1470 mg; about 1430-1480 mg; about1440-1490 mg; about 1450-1500 mg; about 1460-1510 mg; about 1470-1520mg; about 1480-1530 mg; about 1490-1540 mg; about 1500-1550 mg; about1510-1560 mg; about 1520-1570 mg; about 1530-1580 mg; about 1540-1590mg; about 1550-1600 mg; about 1560-1610 mg; about 1570-1620 mg; about1580-1630 mg; about 1590-1640 mg; about 1600-1650 mg; about 1610-1660mg; about 1620-1670 mg; about 1630-1680 mg; about 1640-1690 mg; about1650-1700 mg; about 1660-1710 mg; about 1670-1720 mg; about 1680-1730mg; about 1690-1740 mg; about 1700-1750 mg; about 1710-1760 mg; about1720-1770 mg; about 1730-1780 mg; about 1740-1790 mg; about 1750-1800mg; about 1760-1810 mg; about 1770-1820 mg; about 1780-1830 mg; about1790-1840 mg; about 1800-1850 mg; about 1810-1860 mg; about 1820-1870mg; about 1830-1880 mg; about 1840-1890 mg; about 1850-1900 mg; about1860-1910 mg; about 1870-1920 mg; about 1880-1930 mg; about 1890-1940mg; about 1900-1950 mg; about 1910-1960 mg; about 1920-1970 mg; about1930-1980 mg; about 1940-1990 mg; about 1950-2000 mg; about 1960-2010mg; about 1970-2020 mg; about 1980-2030 mg; about 1990-2040 mg; about2000-2050 mg; about 2010-2060 mg; about 2020-2070 mg; about 2030-2080mg; about 2040-2090 mg; about 2050-2100 mg; about 2060-2110 mg; about2070-2120 mg; about 2080-2130 mg; about 2090-2140 mg; about 2100-2150mg; about 2110-2160 mg; about 2120-2170 mg; about 2130-2180 mg; about2140-2190 mg; about 2150-2200 mg; about 2160-2210 mg; about 2170-2220mg; about 2180-2230 mg; about 2190-2240 mg; about 2200-2250 mg; about2210-2260 mg; about 2220-2270 mg; about 2230-2280 mg; about 2240-2290mg; about 2250-2300 mg; about 2260-2310 mg; about 2270-2320 mg; about2280-2330 mg; about 2290-2340 mg; about 2300-2350 mg; about 2310-2360mg; about 2320-2370 mg; about 2330-2380 mg; about 2340-2390 mg; about2350-2400 mg; about 40-400 mg; about 50-200 mg; about 200-240 mg; about240-280 mg; about 280-320 mg; about 320-360 mg; about 360-400 mg; about400-450 mg; about 450-500 mg; about 500-600 mg; about 250-350 mg; about100-600 mg; about 40-2000 mg; about 40-800 mg; about 100-900 mg; about100-800 mg; about 40-1000 mg; about 50-1000 mg; about 100-1000 mg; about10-80 mg; about 10-40 mg; about 20-30 mg; or any monthly dose in a rangebounded by, or between, any of these values. A monthly dose may be givenas a single dose, or as two or more individual doses administered duringthe month. In some embodiments, the monthly dose is administeredbi-weekly in 2 or 3 divided doses. In some embodiments, the monthly doseis administered weekly in 4 or 5 divided doses. In some embodiments, themonthly dose is administered daily in 28 to 31 divided doses, or in 56to 62 divided doses or more. In some embodiments, the monthly dose isadministered in 5 to 15 individual doses during the month. The monthlydose may be administered for only 1 month, or may be repeatedlyadministered for 2, 3, 4, 5, 6, or more months.

In other embodiments, the dosage form may be administered weekly forabout one, two, three, four, or more consecutive weeks, every other weekor bi-weekly or once every three weeks. This regimen may be repeatedonce weekly, twice in a month, three times in a month, once monthly,once every two months, once every three months, or as directed by amedical professional.

In certain embodiments, administering the pharmaceutical compositionresults in improvement of pharmacokinetics, for example in fasted humansubjects, such as increased bioavailability (e.g., reduced T_(max),increased C_(max), increased AUC, etc.) of a drug, such as meloxicam oranother NSAID, rizatriptan, frovatriptan, or another triptan, in thedosage form as compared to a dosage form containing the drug but notcontaining a cyclodextrin, an acid inhibitor, or a buffering agent (suchas a bicarbonate). In some embodiments, the bioavailability of the drugwill increase with repeated dosing. For example, the bioavailability ofthe drug (such as meloxicam or another NSAID, rizatriptan, frovatriptan,or another triptan) in the dosage form, for example in fasted humansubjects, may increase after about 1-10 days of repeated dosing; about2-6 days of repeated dosing; about 3-5 days of repeated dosing; about4-6 days of repeated dosing; about 5-8 days of repeated dosing; about 5days of repeated dosing; about 6 days of repeated dosing; about 7 daysof repeated dosing; about 8 days of repeated dosing; about 10 days ofrepeated dosing; about 15 days of repeated dosing; or time period in anyrange bounded by, or between, any of these values; as compared to thebioavailability of the drug in a dosage form not containing acyclodextrin, an acid inhibitor, or a buffering agent (such as abicarbonate). Administering a drug in any dosage forms described hereinto a human subject or patient may improve or achieve the desired oralpharmacokinetic properties of the drug.

Any reference to T_(max), C_(max), AUC, or any other pharmacokineticparameter should be understood to include an average, mean, or medianvalue in human beings, such as human patients or human subjects.

Administering some of the dosage forms to a human being may result in adesired range for an area under the plasma concentration curve (AUC) ofmeloxicam. For example the dosage forms with meloxicam may result in anAUC of meloxicam, such as a median, mean, or average AUC of meloxicam inhuman beings, of about 1-150 μg·hr/mL; about 10-30 μg·hr/mL; about 20-40μg·hr/mL; about 30-50 μg·hr/mL; about 40-60 μg·hr/mL; about 50-70μg·hr/mL; about 60-80 μg·hr/mL; about 70-90 μg·hr/mL; about 80-100μg·hr/mL; about 10-100 μg·hr/mL; about 50-150 μg·hr/mL; about 25-125μg·hr/mL; about 75-150 μg·hr/mL; about 20-50 μg·hr/mL; about 40-70μg·hr/mL; about 60-90 μg·hr/mL; about 80-110 μg·hr/mL; about 100-130μg·hr/mL; about 120-150 μg·hr/mL; about 100-150 μg·hr/mL; or any AUC ina range bounded by, or between, any of these values.

Administering some of the dosage forms to a human being may result in adesired range for an area under the plasma concentration curve (AUC) offrovatriptan. For example the dosage forms with frovatriptan or anothertriptan may result in an AUC of frovatriptan, such as a median, mean, oraverage AUC of frovatriptan in human beings, or another triptan of about1-150 μg·hr/mL; about 10-30 μg·hr/mL; about 20-40 μg·hr/mL; about 30-50μg·hr/mL; about 40-60 μg·hr/mL; about 50-70 μg·hr/mL; about 60-80μg·hr/mL; about 70-90 μg·hr/mL; about 80-100 μg·hr/mL; about 10-100μg·hr/mL; about 50-150 μg·hr/mL; about 25-125 μg·hr/mL; about 75-150μg·hr/mL; about 20-50 μg·hr/mL; about 40-70 μg·hr/mL; about 60-90μg·hr/mL; about 80-110 μg·hr/mL; about 100-130 μg·hr/mL; about 120-150μg·hr/mL; or any AUC in a range bounded by, or between, any of thesevalues.

Unless otherwise indicated, the AUC refers to the AUC calculated to thelast measured concentration (AUC_(0-t)), over a period of 24 hours(AUC₀₋₂₄), or extrapolated to infinity (AUC_(0-inf)).

For some acute pain conditions, such as migraine and other types ofheadache, the AUC for a short period after oral administration, such asan AUC measured over 6 hours (or AUC₀₋₆), may be of particular interest,e.g. for quick pain relief. For example, some dosage forms may result inan AUC₀₋₆ of meloxicam, such as a median, mean, or average AUC₀₋₆ ofmeloxicam in human beings, that is at least about 6 μg·hr/mL (or 6,000ng·hr/mL); at least about 7 μg·hr/mL (or 7,000 ng·hr/mL); at least about8 μg·hr/mL (or 8,000 ng·hr/mL); at least about 9 μg·hr/mL (or 9,000ng·hr/mL); about 6-10 μg·hr/mL; about 7-11 μg·hr/mL; about 8-12μg·hr/mL; about 9-13 μg·hr/mL; or any AUC₀₋₆ in a range bounded by, orbetween, any of these values.

In some embodiments, the dosage form may result in a C_(max) ofmeloxicam, such as a median, mean, or average C_(max) of meloxicam inhuman beings, of about 10-2500 ng/mL; about 100-2250 ng/mL; about500-2000 ng/mL; about 1000-2500 ng/mL; about 1000-2000 ng/mL; about100-900 ng/mL; about 750-1500 ng/mL; about 1250-2000 ng/mL; about1500-2300 ng/mL; about 800-1200 ng/mL; about 1900-2400 ng/mL; about50-500 ng/mL; about 400-950 ng/mL; about 900-1500 ng/mL; about 1100-2200ng/mL; about 1300-1600 ng/mL; about 1200-1500 ng/mL; about 1400-2100ng/mL; about 1500-1900 ng/mL; about 1600-2100 ng/mL; about 1700-2000ng/mL; about 1900-2500 ng/mL; about 1500-1700 ng/mL; about 1600-1800ng/mL; about 1700-1900 ng/mL; about 1800-2000 ng/mL; about 1900-2100ng/mL; about 2000-2200 ng/mL; about 2100-2300 ng/mL; about 2200-2400ng/mL; about 2300-2500 ng/mL; about 2500-3000 ng/mL; at least about 1400ng/mL; at least about 1500 ng/mL; at least about 1600 ng/mL; at leastabout 1700 ng/mL; at least about 1800 ng/mL; at least about 1900 ng/mL;at least about 2000 ng/mL; at least about 2100 ng/mL; at least about2200 ng/mL; at least about 2300 ng/mL; at least about 2400 ng/mL; atleast about 2500 ng/mL; or any C_(max) in a range bounded by, orbetween, any of these values.

In some embodiments, the dosage form may result in a C_(max) offrovatriptan, such as a median, mean, or average C_(max) of frovatriptanin human beings, of about 10-2500 ng/mL; about 100-2250 ng/mL; about500-2000 ng/mL; about 1000-2500 ng/mL; about 1000-2000 ng/mL; about100-900 ng/mL; about 750-1500 ng/mL; about 1250-2000 ng/mL; about1500-2300 ng/mL; about 800-1200 ng/mL; about 1900-2400 ng/mL; about50-500 ng/mL; about 400-950 ng/mL; about 900-1500 ng/mL; about 1100-2200ng/mL; about 1300-1600 ng/mL; about 1200-1500 ng/mL; about 1400-2100ng/mL; about 1500-1900 ng/mL; about 1600-2100 ng/mL; about 1700-2000ng/mL; about 1900-2500 ng/mL; about 150-1700 ng/mL; about 1600-1800ng/mL; about 1700-1900 ng/mL; about 1800-2000 ng/mL; about 1900-2100ng/mL; about 2000-2200 ng/mL; about 2100-2300 ng/mL; about 2200-2400ng/mL; about 2300-2500 ng/mL; about 2500-3000 ng/mL; or any C_(max) in arange bounded by, or between, any of these values.

For example, a method described herein may reduce the T_(max) ofmeloxicam, such as a median, mean, or average T_(max) of meloxicam inhuman beings. In some embodiments, the method may include treating apatient to achieve the T_(max) of meloxicam in the patient within about10 minutes; within about 20 minutes; within about 30 minutes; withinabout 40 minutes; within about 50 minutes; within about 60 minutes;within about 70 minutes; within about 80 minutes; within about 90minutes; within about 100 minutes; within about 110 minutes; withinabout 120 minutes; within about 180 minutes; about 10-30 minutes; about20-40 minutes, about 30-50 minutes, about 40-60 minutes; about 50-70minutes; about 60-90 minutes; about 70-100 minutes; about 80-110minutes; about 90-120 minutes; about 1-10 hr; about 2-9 hr; about 3-7hr; about 4-6 hr; about 1-5 hr; about 2-7 hr; about 3-8 hr; about 4-9hr; about 1-4 hr; about 2-5 hr; about 3-6 hr; about 4-7 hr; about 5-8hr; about 6-9 hr; about 7-10 hr; or any T_(max) in a range bounded by,or between, any of these values; after administration of the dosageforms described above.

In some embodiments, an oral dosage form may have a T_(max) ofmeloxicam, such as a median, mean, or average T_(max) of meloxicam inhuman being, that is shorter than would be achieved by administeringmeloxicam by intramuscular injection. In some embodiments, an oraldosage form may have a T_(max) of meloxicam that is shorter, or mayincrease meloxicam plasma levels at a faster rate, by a factor of atleast about 1.5, about 2, about 3, about 4, about 5, about 6, about 7,about 8, about 9, about 10, about 12, about 15, about 20, or by a factorof about 1.1-2, about 1.5-3, about 2-4, about 3-5, about 4-6, about1.5-1000, about 2-100, about 3-100, about 4-100, about 5-100, about6-100, about 7-100, about 8-100, about 9-100, about 10-100, about12-100, about 15-100, about 20-100, or by a factor in a range bounded byany of these values, as compared to that observed by intramuscularinjection.

In some embodiments, an oral dosage form may have a time to half-maximalplasma concentration of meloxicam, such as a median, mean, or averagetime to half-maximal plasma concentration in human beings, that is lessthan about 5 minutes; less than about 10 minutes; less than about 15minutes; less than about 20 minutes; less than about 25 minutes; lessthan about 30 minutes; less than about 35 minutes; less than about 40minutes; less than about 45 minutes; less than about 50 minutes; lessthan about 55 minutes; less than about 60 minutes; less than about 90minutes; about 5-15 minutes; about 10-20 minutes, about 15-25 minutes,about 20-30 minutes; about 25-35 minutes; about 30-45 minutes; about35-50 minutes; about 40-55 minutes; about 45-60 minutes; about 0.5-5hours; or any time in a range bounded by any of these values.

For example, a method described herein may reduce the T_(max) offrovatriptan, such as a median, mean, or average T_(max) of frovatriptanin human beings. In some embodiments, the method may include treating apatient to achieve the T_(max) of frovatriptan in the patient withinabout 10 minutes; about 20 minutes; about 30 minutes; about 40 minutes;about 50 minutes; about 60 minutes; about 70 minutes; about 80 minutes;about 90 minutes; about 100 minutes; about 110 minutes; about 120minutes; about 180 minutes; about 10-30 minutes; about 20-40 minutes;about 30-50 minutes; about 40-60 minutes; about 50-70 minutes; about60-80 minutes; about 70-90 minutes; about 0.1-1 hour; about 0.1-0.5hour; about 0.5-1 hour; about 1-10 hr; about 2-9 hr; about 3-7 hr; about4-6 hr; about 1-5 hr; about 2-7 hr; about 3-8 hr; about 4-9 hr; about1-4 hr; about 2-5 hr; about 3-6 hr; about 4-7 hr; about 5-8 hr; about6-9 hr; about 7-10 hr; after administration or any T_(max) in a rangebounded by, or between, any of these values.

In some embodiments, a dosage form comprising meloxicam may result in aplasma concentration of meloxicam, such as a median, mean, or averageplasma concentration of meloxicam in human beings, at 12 hours that isabout 0.01-0.5 μg/mL; about 0.5-0.7 μg/mL; about 0.6-0.8 μg/mL; about0.7-0.9 μg/mL; about 0.8-1 μg/mL; about 0.01-1 μg/mL; about 0.9-1.1μg/mL; about 1-1.2 μg/mL; about 1.1-1.3 μg/mL; about 1.2-1.4 μg/mL;about 1.3-1.5 μg/mL; about 1-1.5 μg/mL; about 1.4-1.6 μg/mL; about1.5-1.7 μg/mL; about 1.6-1.8 μg/mL; about 1.7-1.9 μg/mL; about 1.8-2μg/mL; about 1.5-2 μg/mL; about 1.9-2.1 μg/mL; about 2-2.2 μg/mL; about2.1-2.3 μg/mL; about 2.2-2.4 μg/mL; about 2.3-2.5 μg/mL; about 2-2.5μg/mL; about 2.4-2.6 μg/mL; about 2.5-2.7 μg/mL; about 2.6-2.8 μg/mL;about 2.7-2.9 μg/mL; about 2.8-3 μg/mL; about 2.5-3 μg/mL; about 2.9-3.1μg/mL; about 3-3.2 μg/mL; about 3.1-3.3 μg/mL; about 3.2-3.4 μg/mL;about 3.3-3.5 μg/mL; about 3-3.5 μg/mL; about 3.4-3.6 μg/mL; about3.5-3.7 μg/mL; about 3.6-3.8 μg/mL; about 3.7-3.9 μg/mL; about 3.8-4μg/mL; about 3.5-4 μg/mL; or any plasma concentration of meloxicam at 12hours in a range bounded by, or between, any of these values.

In some embodiments, meloxicam is administered at a dose that results ina meloxicam average plasma level (such as a C_(ave), or average plasmalevel) of about 0.01-0.5 μg/mL; about 0.5-0.7 μg/mL; about 0.6-0.8μg/mL; about 0.7-0.9 μg/mL; about 0.8-1 μg/mL; about 0.01-1 μg/mL; about0.9-1.1 μg/mL; about 1-1.2 μg/mL; about 1.1-1.3 μg/mL; about 1.2-1.4μg/mL; about 1.3-1.5 μg/mL; about 1.4-1.6 μg/mL; about 1.5-1.7 μg/mL;about 1.6-1.8 μg/mL; about 1.7-1.9 μg/mL; about 1.8-2 μg/mL; about 1-2μg/mL; about 0.01-3 μg/mL; about 1.9-2.1 μg/mL; about 2-2.2 μg/mL; about2.1-2.3 μg/mL; about 2.2-2.4 μg/mL; about 2.3-2.5 μg/mL; about 2.4-2.6μg/mL; about 2.5-2.7 μg/mL; about 2.6-2.8 μg/mL; about 2.7-2.9 μg/mL;about 2.8-3 μg/mL; about 2-3 μg/mL; about 2.9-3.1 μg/mL; about 3-3.2μg/mL; about 3.1-3.3 μg/mL; about 3.2-3.4 μg/mL; about 3.3-3.5 μg/mL;about 3.4-3.6 μg/mL; about 3.5-3.7 μg/mL; about 3.6-3.8 μg/mL; about3.7-3.9 μg/mL; about 3.8-4 μg/mL; about 3-4 μg/mL; about 2-4 μg/mL;about 0.01-4 μg/mL; about 0.1-20 μg/mL; about 0.5-15 μg/mL; about 0.5-10μg/mL; about 5-15 μg/mL; about 10-20 μg/mL; about 7.5-15 μg/mL; about2-10 μg/m L; about 1-8 μg/mL; about 1-6 μg/mL; about 1-2 μg/mL; about0.5-3.5 μg/mL; about 0.5-7 μg/mL; about 12-20 μg/mL; about 8-12 μg/mL;about 1-4 μg/mL; about 4-7 μg/mL; about 7-11 μg/mL; about 11-15 μg/mL;about 15-19 μg/mL; about 16-20 μg/mL; or any meloxicam average plasmalevel in a range bounded by, or between, any of these values.

In some embodiments, a dosage form comprising frovatriptan may result ina plasma concentration of frovatriptan at 12 hours that is about0.01-0.5 μg/mL; about 0.5-0.7 μg/mL; about 0.6-0.8 μg/mL; about 0.7-0.9μg/mL; about 0.8-1 μg/mL; about 0.9-1.1 μg/mL; about 1-1.2 μg/mL; about1.1-1.3 μg/mL; about 1.2-1.4 μg/mL; about 1.3-1.5 μg/mL; about 1.4-1.6μg/mL; about 1.5-1.7 μg/mL; about 1.6-1.8 μg/mL; about 1.7-1.9 μg/mL;about 1.8-2 μg/mL; about 1.9-2.1 μg/mL; about 2-2.2 μg/mL; about 2.1-2.3μg/mL; about 2.2-2.4 μg/mL; about 2.3-2.5 μg/mL; about 2.4-2.6 μg/mL;about 2.5-2.7 μg/mL; about 2.6-2.8 μg/mL; about 2.7-2.9 μg/mL; about2.8-3 μg/mL; about 2.9-3.1 μg/mL; about 3-3.2 μg/mL; about 3.1-3.3μg/mL; about 3.2-3.4 μg/mL; about 3.3-3.5 μg/mL; about 3.4-3.6 μg/mL;about 3.5-3.7 μg/mL; about 3.6-3.8 μg/mL; about 3.7-3.9 μg/mL; about3.8-4 μg/mL; or any plasma concentration of frovatriptan at 12 hours ina range bounded by, or between, any of these values.

In some embodiments, frovatriptan is administered at a dose that resultsin an average frovatriptan plasma level (such as a C_(ave), or averageplasma level) of about 0.01-0.5 μg/mL; about 0.5-0.7 μg/mL; about0.6-0.8 μg/mL; about 0.7-0.9 μg/mL; about 0.8-1 μg/mL; about 0.9-1.1μg/mL; about 1-1.2 μg/mL; about 1.1-1.3 μg/mL; about 1.2-1.4 μg/mL;about 1.3-1.5 μg/m L; about 1.4-1.6 μg/mL; about 1.5-1.7 μg/mL; about1.6-1.8 μg/mL; about 1.7-1.9 μg/mL; about 1.8-2 μg/mL; about 1.9-2.1μg/mL; about 2-2.2 μg/mL; about 2.1-2.3 μg/mL; about 2.2-2.4 μg/mL;about 2.3-2.5 μg/mL; about 2.4-2.6 μg/mL; about 2.5-2.7 μg/mL; about2.6-2.8 μg/mL; about 2.7-2.9 μg/mL; about 2.8-3 μg/mL; about 2.9-3.1μg/mL; about 3-3.2 μg/mL; about 3.1-3.3 μg/mL; about 3.2-3.4 μg/mL;about 3.3-3.5 μg/mL; about 3.4-3.6 μg/mL; about 3.5-3.7 μg/mL; about3.6-3.8 μg/mL; about 3.7-3.9 μg/mL; about 3.8-4 μg/mL; about 0.1-20μg/mL; about 0.5-15 μg/mL; about 0.5-10 μg/mL; about 5-15 μg/mL; about10-20 μg/mL; about 7.5-15 μg/mL; about 2-10 μg/mL; about 1-8 μg/mL;about 1-6 μg/mL; about 1-2 μg/mL; about 0.5-3.5 μg/mL; about 0.5-7μg/mL; about 12-20 μg/mL; about 8-12 μg/mL; about 1-4 μg/m L; about 4-7μg/mL; about 7-11 μg/m L; about 11-15 μg/mL; about 15-19 μg/mL; about16-20 μg/mL; or any amount of frovatriptan average plasma level in arange bounded by, or between, any of these values.

In some embodiments, the dosage form may be formulated for oraladministration, for example, with an inert diluent or with an ediblecarrier, or it may be enclosed in hard or soft shell gelatin capsules,compressed into tablets, or incorporated directly with the food of thediet. For oral therapeutic administration, the active compound may beincorporated with an excipient and used in the form of ingestibletablets, buccal tablets, coated tablets, troches, capsules, elixirs,dispersions, suspensions, solutions, syrups, wafers, patches, and thelike.

Tablets, troches, pills, capsules and the like may also contain one ormore of the following: a binder such as gum tragacanth, acacia, cornstarch or gelatin; an excipient, such as dicalcium phosphate; adisintegrating agent such as corn starch, potato starch, alginic acidand the like; a lubricant such as magnesium stearate; a sweetening agentsuch as sucrose, lactose or saccharin; or a flavoring agent such aspeppermint, oil of wintergreen or cherry flavoring. When the unit dosageform is a capsule, it may contain, in addition to materials of the abovetype, a liquid carrier. Various other materials may be present ascoating, for instance, tablets, pills, or capsules may be coated withshellac, sugar or both. A syrup or elixir may contain the activecompound, sucrose as a sweetening agent, methyl and propylparabens aspreservatives, a dye and flavoring, such as cherry or orange flavor. Itmay be desirable for material in a dosage form or pharmaceuticalcomposition to be pharmaceutically pure and substantially non-toxic inthe amounts employed.

Some compositions or dosage forms may be a liquid, or may comprise asolid phase dispersed in a liquid.

The dosage form may further comprise an additional therapeuticallyactive agents, such as an acid inhibitor or an analgesic.

In some embodiments, the dosage form may further comprise an acidinhibitor present in an amount effective to raise the gastric pH of apatient to at least 2, to at least 2.5, to at least 3, to at least 3.5,to at least 4, and more to at least 5, when one or more unit dosageforms are administered. The term “acid inhibitor” refers to agents thatinhibit gastric acid secretion and increase gastric pH. Specific H₂blockers, also referred to as H₂ antagonists or histamine H₂ blockers orantagonists, which may be used include but are not limited tocimetidine, ranitidine, ebrotidine, pabutidine, lafutidine, loxtidine,famotidine, or combinations thereof.

Other agents that may be effectively used as acid inhibitors are theproton pump inhibitors such as omeprazole, esomeprazole, pantoprazole,lansoprazole, dexlansoprazole, rabeprazole, pariprazole, leminoprazoleand tenatoprazole. In some embodiments the daily dose of the acidinhibitor, such as esomeprazole, is about 1-200 mg, about 1-100 mg,about 50-100 mg, about 1-50 mg, about 40-80 mg, about 5-50 mg, about20-40 mg, about 10-50 mg, about 10-20 mg, about 20-40 mg, about 15-50mg, about 30-60 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mgor any other amount in a range bounded by, or between, any of thesevalues.

Examples of particular proton pump inhibitors include esomeprazole,present in unit dosage forms in an amount of between 5 mg and 50 mg;omeprazole, present in unit dosage forms in an amount of between 5 mgand 50 mg; lansoprazole, present in unit dosage forms in an amount ofbetween 5 mg and 150 mg (and preferably at between 5 mg and 30 mg); andpantoprazole, present in unit dosage forms in an amount of between 10 mgand 200 mg. In some embodiments, the proton pump inhibitor (such asesomeprazole) is present in the dosage form in an amount of about 10-30mg, about 20-40 mg, about 30-50 mg, about 40-60 mg, about 50-70 mg,about 60-80 mg, about 70-90 mg, or about 80-100 mg. Recently, a newerclass of acid inhibitor has been developed which competes with potassiumat the acid pump. The compounds in this class have been referred to as“reversible proton pump inhibitors” or “acid pump antagonists” and mayalso be used. Examples include AZD-0865, AR-H047108, CS-526,pumaprazole, revaprazan and soraprazan (see WO9605177 and WO9605199).Other compounds in this group are H-335/25 (AstraZeneca, Dialog file128, accession number 020806); Sch-28080 (Schering Plough, Dialog file128, accession number 009663); Sch-32651 (Schering Plough, Dialog file128, accession number 006883) and SK&F-96067 (CAS Registry no.115607-61-9).

Additional therapeutically active agents may include an analgesic suchas a second non-steroidal anti-inflammatory drug, an opioid, a steroid,a triptan, etc. In some embodiments, the dosage form or treatment alsofurther comprises administering a second non-steroidal anti-inflammatorydrug in an amount effective to reduce or eliminate pain or inflammation.It will be understood that, for the purposes of the present disclosure,reference to an acid inhibitor, NSAID, or analgesic agent will includeall of the common forms of these compounds and, in particular, theirpharmaceutically acceptable salts. The amounts of NSAIDs which aretherapeutically effective may be lower in the current embodiments thanotherwise found in practice due to potential positive kineticinteraction and NSAID absorption in the presence of an acid inhibitor,and or in the presence of a buffering agent.

In other embodiments, the dosage form or treatment may further compriseadministering an opioid in an amount effective to reduce or eliminatepain or inflammation. The opioid may include, but is not limited to,(dextro)propoxyphene, A-methylfentanyl, alfentanil, allylprodine,bezitramide, buprenorphine, butorphanol, carfentanyl, desmethylprodine,dextromoramide, dezocine, diacetylmorphine, dihydrocodeinone,dihydroetorphine, dimorphone, diphenoxylate, dipipanone, etorphine,fentanyl, ketobemidone, lefetamine, levacetylmethadol, levomethorphan,levorphanol, loperamide, meperidine, meptazinol, methadone,methylmorphine, morphine, nalbuphine, nalmefene, naloxone, naltrexone,nicomorphine, ohmefentanyl, oripavine, oxycodone, oxymorphone, PEPAP,paramorphine, pentazocine, phenazocine, piritramide, prodine,remifentanil, sufentanil, tapentadol, tilidine, tramadol, orcombinations thereof.

The term “unit dosage form” as used herein refers to a single entity fordrug administration. For example, a single tablet or capsule combiningboth a triptan and an NSAID would be a unit dosage form. A “unit dosageform” (or “unit dose form”) may also be referred to as a “fixed dosageform” (or “fixed dose form”) or “fixed dosage combination” (or “fixeddose combination”) and are otherwise interchangeable. In one embodiment,the unit dosage form is a multilayer tablet.

In another embodiment, the unit dosage form is suitable for oraladministration to a patient. In yet another embodiment, the unit dosageform is a tablet. In still another embodiment, the unit dosage form is amultilayer tablet comprising a single core and one or more layersoutside of the core. In some embodiments, the pharmaceutical compositionmay have an effective amount of a triptan (such as rizatriptan orfrovatriptan), a cyclodextrin, and a bicarbonate to increasebioavailability of rizatriptan or frovatriptan. In other embodiments,the pharmaceutical composition may have an effective amount of thetriptan, sulfobutylether-β-cyclodextrin (SBEβCD), and sodium bicarbonateto increase bioavailability of the triptan or reduce the T_(max) of thetriptan.

Some dosage forms may comprise a first layer comprising meloxicam, anSBEβCD, and a bicarbonate; and a second layer comprising a triptan and abicarbonate.

The first layer may contain, for example, any amount of meloxicam in oneof the ranges recited above. For example, all of the meloxicam in thedosage form may be present in the first layer. The second layer maycontain all of triptan, such that any amount in the ranges recited abovewith respect to the triptan may apply to the second layer.

In some embodiments, the first layer contains about 10-200 mg, about50-150 mg, about 50-100 mg, about 70-120 mg, about 90-140 mg, or about100 mg of the bicarbonate, such as sodium bicarbonate, or any amount ofthe bicarbonate in a range bounded by any of these values.

In some embodiments, the second layer contains about 100-500 mg, about200-500 mg, about 300-500 mg, about 350-450 mg, about 380-420 mg, orabout 400 mg of the bicarbonate, such as sodium bicarbonate, or anyamount of the bicarbonate in a range bounded by any of these values.

Some oral dosage forms may have enteric coatings or film coatings. Insome embodiments, a dosage form may comprise a tablet or a capsulehaving an enteric coating. In some embodiments, a dosage form maycomprise a tablet or a capsule having a film coating.

An embodiment of the present disclosure is directed to a pharmaceuticalcomposition in unit dosage form suitable for administration to apatient, comprising:

(a) dexketoprofen, which may or may not be surrounded by an entericcoating;

(b) sodium or potassium bicarbonate and/or sodium or potassiumcarbonate; and

(c) frovatriptan, which may or may not be formulated with acyclodextrin, and which may or may not be surrounded by an entericcoating

In certain embodiments, the pharmaceutical composition results in fasterrelease or dissolution of a drug (e.g. meloxicam or another NSAID,rizatriptan, frovatriptan, or another triptan) from the dosage form ascompared to a dosage form containing the same drug but not containingthe acid inhibitor, or not containing the buffering agent.

The following embodiments are contemplated:

Embodiment 1

An inclusion complex of meloxicam in a cyclodextrin.

Embodiment 2

A dosage form comprising: 1) the inclusion complex of embodiment 1, or2) meloxicam and a carbonate or a bicarbonate.

Embodiment 3

The dosage form of embodiment 2 comprising the inclusion complex,wherein the cyclodextrin comprises substituted β-cyclodextrin.

Embodiment 4

The dosage form of embodiment 3, wherein the substituted β-cyclodextrinis a sulfobutyl ether β-cyclodextrin (SBEβCD) or hydroxypropylβ-cyclodextrin (HPBCD).

Embodiment 5

The dosage form of embodiment 4, wherein the cyclodextrin is the SBEβCD.

Embodiment 6

The dosage form of embodiment 5, wherein the SBEβCD has about 6 to about7 sulfobutyl ether groups for each molecule of β-cyclodextrin.

Embodiment 7

The dosage form of embodiment 6, wherein the meloxicam and the SBEβCDhave a molar ratio of about 0.8 to about 1.2.

Embodiment 8

The dosage form of embodiment 6, wherein the meloxicam and the SBEβCDhave a molar ratio of about 1.

Embodiment 9

The dosage form of embodiment 2, 3, 4, 5, 6, 7, or 8, comprising abicarbonate.

Embodiment 10

The dosage form of embodiment 9, wherein the bicarbonate comprisessodium bicarbonate.

Embodiment 11

The dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, or 10, which is anoral dosage form.

Embodiment 12

The dosage form of embodiment 2, 3, 4, 5, 6, 9, 10, or 11, wherein about50 mg to about 200 mg of SBEβCD is present in the dosage form.

Embodiment 13

The dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12,wherein the carbonate or bicarbonate is present in an amount in a rangeof about 400 mg to about 600 mg.

Embodiment 14

The dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13,wherein the T_(max) of meloxicam is decreased as compared to a dosageform not having a carbonate, a bicarbonate, or a cyclodextrin.

Embodiment 15

The method of embodiment 14, wherein the T_(max) of meloxicam isachieved in the patient at a time in a range of about 10 minutes toabout 180 minutes after administration.

Embodiment 16

The dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, or 15, having an oral bioavailability of meloxicam that is higherthan a dosage form not having a carbonate, a bicarbonate, or acyclodextrin.

Embodiment 17

The dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, or 16, further comprising an acid inhibitor.

Embodiment 18

The dosage form of embodiment 17, wherein the acid inhibitor is a protonpump inhibitor.

Embodiment 19

The dosage form of embodiment 18, wherein the proton pump inhibitor isesomeprazole.

Embodiment 20

The dosage form of embodiment 19, wherein about 30 mg to about 50 mg ofesomeprazole is present in the dosage form.

Embodiment 21

A method of administering meloxicam orally, comprising orallyadministering a dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 to a patient in need oftreatment.

Embodiment 22

The method of embodiment 21, wherein the dosage form is administered totreat pain.

Embodiment 23

The method of embodiment 21, wherein the dosage form is administered totreat inflammatory pain.

Embodiment 24

The method of embodiment 21, wherein the dosage form is administered totreat osteoarthritis, rheumatoid arthritis, or juvenile rheumatoidarthritis.

Embodiment 25

A method of administering meloxicam intravenously, comprisingintravenously administering a dosage form of embodiment 2, 3, 4, 5, 6,7, 8, 9, 10, 12, 13, 14, or 15, to a patient in need of treatment.

Embodiment 26

An inclusion complex of frovatriptan in a cyclodextrin.

Embodiment 2-1

A dosage form comprising: 1) the inclusion complex of frovatriptan in acyclodextrin, or 2) frovatriptan and a carbonate or a bicarbonate.

Embodiment 2-2

The dosage form of Embodiment 2-1, comprising the inclusion complex,wherein the cyclodextrin comprises a sulfobutyl ether β-cyclodextrin(SBEβCD) or a hydroxypropyl β-cyclodextrin (HPβCD).

Embodiment 2-3

The dosage form of Embodiment 2-2, wherein the cyclodextrin is theSBEβCD and has about 6 to about 7 sulfobutyl ether groups for eachmolecule of β-cyclodextrin.

Embodiment 2-4

The dosage form of Embodiment 2-3, further comprising a bicarbonate.

Embodiment 2-5

The dosage form of Embodiment 2-4, wherein the bicarbonate comprisessodium bicarbonate.

Embodiment 2-6

The dosage form of Embodiment 2-3, wherein the frovatriptan and theSBEβCD have a molar ratio of about 0.8 to about 1.2.

Embodiment 2-7

The dosage form of Embodiment 2-6, further comprising a bicarbonate.

Embodiment 2-8

The dosage form of Embodiment 2-7, wherein the bicarbonate comprisessodium bicarbonate.

Embodiment 2-9

The dosage form of Embodiment 2-1, which is an oral dosage form.

Embodiment 2-10

The dosage form of Embodiment 2-2, comprising the inclusion complex,wherein about 50 mg to about 200 mg of the SBEβCD is present in a unitdosage form.

Embodiment 2-11

The dosage form of Embodiment 2-1, comprising frovatriptan and thecarbonate or the bicarbonate.

Embodiment 2-12

The dosage form of Embodiment 2-1, wherein the T_(max) of frovatriptanis decreased as compared to a dosage form without a carbonate, abicarbonate, or a cyclodextrin.

Embodiment 2-13

The method of Embodiment 2-1, wherein the T_(max) of frovatriptan isachieved in the patient at a time in a range of about 10 minutes toabout 180 minutes after administration.

Embodiment 2-14

The dosage form of Embodiment 2-1, having an oral bioavailability offrovatriptan that is higher than a dosage form without a carbonate, abicarbonate, or a cyclodextrin.

Embodiment 2-15

The dosage form of Embodiment 2-11, wherein the carbonate or thebicarbonate is present in a unit dosage form at an amount in a range ofabout 400 mg to about 600 mg.

Embodiment 2-16

The dosage form of Embodiment 2-15, wherein the carbonate or thebicarbonate is sodium bicarbonate.

Embodiment 2-17

The dosage form of Embodiment 2-11, further comprising an NSAID.

Embodiment 2-18

The dosage form of Embodiment 2-17, wherein the NSAID is a dexketoprofenor meloxicam.

Embodiment 2-19

The dosage form of Embodiment 2-18, wherein the NSAID is dexketoprofen.

Embodiment 2-20

The dosage form of Embodiment 2-19, wherein about 10 mg to about 50 mgof dexketoprofen is present in a unit dosage form.

Embodiment 2-21

A method of administering frovatriptan orally, comprising orallyadministering the dosage form of Embodiment 2-1 to a patient in need oftreatment.

Embodiment 2-22

The method of Embodiment 2-21, wherein the dosage form comprises theinclusion complex, wherein the cyclodextrin is SBEβCD, and furthercomprises a bicarbonate.

Embodiment 2-23

The method of Embodiment 2-22, wherein the bicarbonate is sodiumbicarbonate.

Embodiment 2-24

The method of Embodiment 2-23, wherein a unit dosage form contains about300 mg to about 600 mg of sodium bicarbonate.

Embodiment 2-25

The method of Embodiment 2-22, wherein the dosage form further comprisesa NSAID.

Embodiment 2-26

The method of Embodiment 2-25, wherein the NSAID is dexketoprofen,meloxicam, naproxen, ibuprofen, or celecoxib.

Embodiment 2-27

The method of Embodiment 2-21, wherein the dosage form is administeredto treat pain.

Embodiment 2-28

The method of Embodiment 2-21, wherein the dosage form is administeredto treat inflammatory pain.

Embodiment 2-29

The method of Embodiment 2-21, wherein the dosage form is administeredto treat osteoarthritis, rheumatoid arthritis, or juvenile rheumatoidarthritis.

Embodiment P-1

A dosage form comprising:

meloxicam;

a sulfobutyl ether β-cyclodextrin (SBEβCD);

a bicarbonate; and

a triptan

wherein the dosage form is an oral dosage form having a shorter T_(max)of meloxicam than a reference dosage form that: 1) contains the sameamount of meloxicam, 2) does not contain an SBEβCD, and 3) does notcontain a bicarbonate.

Embodiment P-2

The dosage form of Embodiment P-1, comprising an inclusion complex of 1)the meloxicam or the triptan and 2) the SBEβCD.

Embodiment P-3

The dosage form of Embodiment P-1 or P-2, containing about 10 mg toabout 20 mg of meloxicam.

Embodiment P-4

The dosage form of Embodiment P-3, containing about 15 mg of meloxicam.

Embodiment P-5

The dosage form of Embodiment P-1, P-2, P-3, or P-4, wherein the SBEβCDhas about 6 to about 7 sulfobutyl ether groups for each molecule ofβ-cyclodextrin.

Embodiment P-6

The dosage form of Embodiment P-1, P-2, P-3, P-4, or P-5, containingabout 50 mg to about 200 mg of the SBEβCD.

Embodiment P-7

The dosage form of Embodiment P-1, P-2, P-3, P-4, P-5, or P-6, whereinthe triptan is rizatriptan.

Embodiment P-8

The dosage form of Embodiment P-7, containing about 5 mg to about 20 mgof rizatriptan.

Embodiment P-9

The dosage form of Embodiment P-8, containing about 10 mg ofrizatriptan.

Embodiment P-10

The dosage form of Embodiment P-6, containing about 100 mg of SBEβCD.

Embodiment P-11

The dosage form of Embodiment P-1, P-2, P-3, P-4, P-5, P-6, P-7, P-8,P-9, or P-10, wherein the bicarbonate comprises sodium bicarbonate.

Embodiment P-12

The dosage form of Embodiment P-10, containing about 400 mg to about 600mg of the bicarbonate.

Embodiment P-13

The dosage form of Embodiment P-12, containing about 500 mg of sodiumbicarbonate.

Embodiment P-14

The dosage form of Embodiment P-1, P-2, P-3, P-4, P-5, P-6, P-7, P-8,P-9, P-10, P-11, or P-12, wherein the oral dosage form has been shown tohave a mean T_(max) of meloxicam that is less than about 3 hours.

Embodiment P-15

The dosage form of Embodiment P-14, wherein the oral dosage form hasbeen shown to have a mean T_(max) of meloxicam that is less than about 2hours.

Embodiment P-16

The dosage form of Embodiment P-14, wherein the oral dosage form hasbeen shown to have a mean T_(max) of meloxicam that is less than about 1hour.

Embodiment P-17

The dosage form of Embodiment P-1, P-2, P-3, P-4, P-5, P-6, P-7, P-8,P-9, P-10, P-11, P-12, P-13, P-14, P-15, or P-16, wherein the oraldosage form has increased bioavailability of meloxicam as compared tothe reference dosage form when administered to a mammal.

Embodiment P-18

The dosage form of Embodiment P-1, P-2, P-3, P-4, P-5, P-6, P-7, P-8,P-9, P-10, P-11, P-12, P-13, P-14, P-15, P-16, or P-17, wherein the oraldosage form has improved pharmacokinetics of meloxicam as compared tothe reference dosage form when administered to a mammal.

Embodiment P-19

The dosage form of Embodiment P-1, P-2, P-3, P-4, P-5, P-6, P-7, P-8,P-9, P-10, P-11, P-12, P-13, P-14, P-15, P-16, P-17, or P-18, whereinthe oral dosage form has increased bioavailability of the triptan ascompared to the reference dosage form when administered to a mammal.

Embodiment P-20

The dosage form of Embodiment P-1, P-2, P-3, P-4, P-5, P-6, P-7, P-8,P-9, P-10, P-11, P-12, P-13, P-14, P-15, P-16, P-17, P-18, or P-19,wherein the oral dosage form has improved pharmacokinetics of thetriptan as compared to the reference dosage form when administered to amammal.

Embodiment P-21

A method of improving the pharmacokinetics of a triptan or an NSAID,comprising orally administering a dosage form of Embodiment P-1, P-2,P-3, P-4, P-5, P-6, P-7, P-8, P-9, P-10, P-11, P-12, P-13, P-14, P-15,P-16, P-17, P-18, P-19, or P-20 to a mammal or human being in need oftreatment with the triptan or the NSAID.

Embodiment P-22

The method of treating pain, comprising orally administering a dosageform of Embodiment P-1, P-2, P-3, P-4, P-5, P-6, P-7, P-8, P-9, P-10,P-11, P-12, P-13, P-14, P-15, P-16, P-17, P-18, P-19, or P-20 to amammal or human being in need thereof.

Embodiment P-23

The method of Embodiment P-22, wherein the pain is migraine.

Embodiment P-24

The method of Embodiment P-22, wherein the pain is inflammatory pain.

Example 1

The effect of varying amounts of potassium carbonate (K₂CO₃) and sodiumbicarbonate (NaHCO₃) on the pH of acidic media was tested. The acidicmedia was chosen to simulate gastric conditions. K₂CO₃ or NaHCO₃ wasadded to 50 mL of a 0.01 N HCl solution (pH 2). The pH of the solutionwas measured after addition of the K₂CO₃ or NaHCO₃. Deionized water (240mL) was then added to the mixture and pH was measured again. The resultsare shown in Tables 1-4.

TABLE 1 Results with K₂CO₃ (0.01N HCl) K₂CO₃ (mg) pH 25 2.84 35 6.29 458.05 50 8.29 100 9.43 200 10.14 300 10.39 400 10.55 450 10.58

TABLE 2 Results with K₂CO₃ (0.01N HCl + Water) K₂CO₃ (mg) pH 200 10.27300 10.46 400 10.57 450 10.63

TABLE 3 Results with NaHCO₃ (0.01N HCl) NaHCO₃ (mg) pH 200 5.28 300 5.90400 6.44 450 6.86 500 8.23 750 8.30 1000 8.36

TABLE 4 Results with NaHCO₃ (0.01N HCl + Water) NaHCO₃ (mg) pH 200 5.41300 5.89 400 6.11 450 6.46 500 8.33 750 8.54 1000 8.60

Example 2

Tablets containing meloxicam and combinations of cyclodextrin, K₂CO3, orNaHCO₃ were manufactured and tested for dissolution. Tablets containingmeloxicam alone (MOBIC®) were purchased and also tested for dissolution.The tested tablets are listed in Table 5. Meloxicam in the form ofmeloxicam/cyclodextrin inclusion complexes was used in the tabletscontaining meloxicam and cyclodextrin. The inclusion complexes wereformed by mixing meloxicam and cyclodextrin in an aqueous pH-adjustedsolution. The pH of the solution was adjusted using buffering agents.The resulting soluble meloxicam/cyclodextrin inclusion complexes werethen spray dried. This spray-dried dispersion was used in themanufacture of the tablets containing cyclodextrin.

TABLE 5 Tablets Tablet A 15 mg meloxicam + 25 mg K₂CO3 Tablet B 15 mgmeloxicam + 50 mg K₂CO3 Tablet C 15 mg meloxicam + 100 mg K₂CO3 Tablet D15 mg meloxicam + 150 mg K₂CO3 Tablet E 15 mg meloxicam + 500 mg NaHCO3Tablet F 15 mg meloxicam + 100 mg SBEβCD Tablet G 15 mg meloxicam + 100mg SBEβCD + 25 mg K₂CO3 Tablet H 15 mg meloxicam + 100 mg SBEβCD + 50 mgK₂CO3 Tablet I 15 mg meloxicam + 100 mg SBEβCD + 100 mg K₂CO3 Tablet J15 mg meloxicam + 100 mg SBEβCD + 150 mg K₂CO3 Tablet K 15 mgmeloxicam + 100 mg SBEβCD + 500 mg NaHCO3 Tablet L 15 mg meloxicam(MOBIC ®)

Dissolution testing in acidic medium (chosen to simulate gastricconditions) was performed by placing the tablets in a 0.01 N HClsolution, at an agitation rate of 75 RPM, and vessel temperature ofapproximately 37° C. The results are presented in Tables 6 and in FIGS.1-10. Results at various time points (0, 15, 30, 45, 60, 90, and 120minutes) are presented as percent (%) of meloxicam dissolved.

TABLE 6 Dissolution Results 0 15 30 45 60 90 120 mins mins mins minsmins mins mins Tablet A 0% 23% 17% 15% 13% 12% 11% Tablet B 0% 27% 20%17% 16% 17% 15% Tablet C 0% 31% 26% 25% 24% 23% 21% Tablet D 0% 30% 26%25% 24% 23% 22% Tablet E 0% 50% 66% 77% 84% 92% 95% Tablet F 0% 26% 17%14% 12% 11% 10% Tablet G 0% 48% 39% 26% 20% 16% 14% Tablet H 0% 44% 30%22% 17% 16% 13% Tablet I 0% 32% 33% 27% 21% 16% 15% Tablet J 0% 26% 27%19% 15% 12% 11% Tablet K 0% 85% 86% 86% 86% 86% 86% Tablet L 0%  2%  2% 2%  2%  2%  2%

Dissolution of meloxicam was greater with the tablets containing variouscombinations of meloxicam and cyclodextrin, K₂CO₃, or NaHCO₃, ascompared to tablets containing meloxicam alone. For example, after 120minutes, dissolution of meloxicam tablets containing NaHCO₃ was 95% ascompared to 2% for tablets containing meloxicam alone.

Dissolution of meloxicam increases with increasing amounts of K₂CO₃ inthe absence of cyclodextrin. However, in the presence of cyclodextrin,increasing amounts of K₂CO₃ did not appear to increase meloxicamdissolution. At the highest dose of potassium carbonate tested,meloxicam dissolution in the presence of cyclodextrin was reduced byapproximately 50% as compared to meloxicam dissolution in the absence ofcyclodextrin at 120 minutes.

Dissolution of meloxicam with NaHCO₃ was significantly greater than thatobserved with the highest dose of K₂CO₃ at 15 minutes (50% versus 30%),and at 120 minutes (92% versus 23%). Meloxicam dissolution in thepresence of cyclodextrin was also significantly greater with NaHCO₃ ascompared to the highest dose of K₂CO₃ at 15 minutes (85% versus 26%),and at 120 minutes (86% versus 12%). NaHCO₃ in the presence ofcyclodextrin increased meloxicam dissolution at 15 minutes as comparedto potassium bicarbonate which resulted in a reduction in dissolution.

Example 3

A bilayer tablet containing 1) an inclusion complex of SBEβCD withmeloxicam, and 2) sodium bicarbonate that was prepared(SBEβCD-Meloxicam/Bicarbonate). The first layer contained an inclusioncomplex of 15 mg meloxicam and 100 mg SBEβCD, and 100 mg of sodiumbicarbonate. The second layer contained 40 mg of esomeprazole and 400 mgof sodium bicarbonate.

A total of 20 human subjects were randomly assigned in a 1:1 ratio totreatment with the SBEβCD-Meloxicam/Bicarbonate tablets described aboveor Mobic® tablets (15 mg meloxicam), once daily for 6 days under fastingconditions.

On the first day of dosing, plasma samples were collected forconcentration analysis of meloxicam at several time points.Concentrations of meloxicam were determined using LC-MS/MS.Pharmacokinetic parameters were calculated. The results are depicted inFIG. 11.

The median T_(max) for meloxicam, the trial's primary endpoint, was 9times faster for the SBEβCD-Meloxicam/Bicarbonate tablets as compared toMobic® (0.5 hour versus 4.5 hours respectively, p<0.0001).

The SBEβCD-Meloxicam/Bicarbonate tablets also demonstrated higher meanmaximum plasma concentration (C_(max)) (p=0.0018), faster time totherapeutic plasma concentration (p<0.0001), and faster time tohalf-maximal plasma concentration (p<0.0001) as compared to Mobic®.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, reaction conditions,and so forth used in the specification and claims are to be understoodin all instances as indicating both the exact values as shown and asbeing modified by the term “about.” Accordingly, unless indicated to thecontrary, the numerical parameters set forth in the specification andattached claims are approximations that may vary depending upon thedesired properties sought to be obtained. At the very least, and not asan attempt to limit the application of the doctrine of equivalents tothe scope of the claims, each numerical parameter should at least beconstrued in light of the number of reported significant digits and byapplying ordinary rounding techniques.

The terms “a,” “an,” “the” and similar referents used in the context ofdescribing the invention (especially in the context of the followingclaims) are to be construed to cover both the singular and the plural,unless otherwise indicated herein or clearly contradicted by context.All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext. The use of any and all examples, or exemplary language (e.g.,“such as”) provided herein is intended merely to better illuminate theinvention and does not pose a limitation on the scope of any claim. Nolanguage in the specification should be construed as indicating anynon-claimed element essential to the practice of the invention.

Groupings of alternative elements or embodiments disclosed herein arenot to be construed as limitations. Each group member may be referred toand claimed individually or in any combination with other members of thegroup or other elements found herein. It is anticipated that one or moremembers of a group may be included in, or deleted from, a group forreasons of convenience and/or patentability. When any such inclusion ordeletion occurs, the specification is deemed to contain the group asmodified thus fulfilling the written description of all Markush groupsused in the appended claims.

Certain embodiments are described herein, including the best mode knownto the inventors for carrying out the invention. Of course, variationson these described embodiments will become apparent to those of ordinaryskill in the art upon reading the foregoing description. The inventorexpects skilled artisans to employ such variations as appropriate, andthe inventors intend for the invention to be practiced otherwise thanspecifically described herein. Accordingly, the claims include allmodifications and equivalents of the subject matter recited in theclaims as permitted by applicable law. Moreover, any combination of theabove-described elements in all possible variations thereof iscontemplated unless otherwise indicated herein or otherwise clearlycontradicted by context.

In closing, it is to be understood that the embodiments disclosed hereinare illustrative of the principles of the claims. Other modificationsthat may be employed are within the scope of the claims. Thus, by way ofexample, but not of limitation, alternative embodiments may be utilizedin accordance with the teachings herein. Accordingly, the claims are notlimited to embodiments precisely as shown and described.

1. A method of treating migraine comprising: orally administering adosage form to a human being suffering from migraine, wherein the dosageform comprises a combination of: 1) a complex of meloxicam with asulfobutyl ether β-cyclodextrin (SBEβCD), 2) a bicarbonate, and 3) arizatriptan; wherein the dosage form contains 400 mg to 600 mg of thebicarbonate, about 5 mg to about 50 mg of meloxicam, and about 50 mg toabout 200 mg of the SBEβCD; wherein the dosage form is a solid oraldosage form having a shorter T_(max) of meloxicam in the human beingthan a reference dosage form that: 1) contains the same amount ofmeloxicam, 2) does not contain an SBEβCD, and 3) does not contain abicarbonate; and wherein the human being experiences more pain relief attwo hours after the dosage form is administered as compared to: a) thepain relief that the human being would have experienced two hours afterreceiving a first reference dosage form containing the same amount ofmeloxicam without the rizatriptan, and b) the pain relief that the humanbeing would have experienced two hours after receiving a secondreference dosage form containing the same amount of the rizatriptanwithout meloxicam.
 2. The method of claim 1, wherein about 1 mg to about50 mg of the rizatriptan is present in the oral dosage form based uponthe weight of the rizatriptan in the free base form.
 3. The method ofclaim 1, wherein the rizatriptan is present in a salt form in an amountthat is a molar equivalent of about 10 mg of the rizatriptan in the freebase form.
 4. The method of claim 3, wherein the rizatriptan is presentas rizatriptan benzoate.
 5. The method of claim 1, wherein the oraldosage form contains about 10 mg to about 30 mg of meloxicam.
 6. Themethod of claim 1, wherein the oral dosage form contains about 20 mg ofmeloxicam.
 7. The method of claim 1, wherein the oral dosage formcontains about 15 mg of meloxicam.
 8. The method of claim 1, wherein theSBEβCD has about 6 to about 7 sulfobutyl ether groups for each moleculeof β-cyclodextrin.
 9. The method of claim 1, wherein the SBEβCD hasabout 6 sulfobutyl ether groups for each molecule of β-cyclodextrin. 10.The method of claim 1, wherein the SBEβCD has about 7 sulfobutyl ethergroups for each molecule of β-cyclodextrin.
 11. The method of claim 1,wherein the oral dosage form contains about 50 mg to about 150 mg of theSBEβCD.
 12. The method of claim 1, wherein the oral dosage form containsabout 100 mg of the SBEβCD.
 13. The method of claim 1, wherein the molarratio of the SBEβCD to meloxicam is about 0.5 to about
 2. 14. The methodof claim 1, wherein the molar ratio of the SBEβCD to meloxicam is about0.8 to about 1.2.
 15. The method of claim 1, wherein the molar ratio ofthe SBEβCD to meloxicam is about
 1. 16. The method of claim 1, whereinthe oral dosage form contains about 10 mg to about 40 mg meloxicam, andabout 5 mg to about 50 mg of rizatriptan.
 17. The method of claim 1,wherein the oral dosage form contains SBEβCD that is in a weight ratioto rizatriptan that is within a range of about 1 to about
 100. 18. Themethod of claim 17, wherein the oral dosage form contains SBEβCD that isin a weight ratio to rizatriptan that is about
 10. 19. The method ofclaim 17, wherein the oral dosage form contains about 20 mg ofmeloxicam.
 20. The method of claim 1, wherein the bicarbonate comprisessodium bicarbonate.
 21. The method of claim 20, wherein the oral dosageform contains 500 mg of sodium bicarbonate.
 22. The method of claim 1,wherein the oral dosage form has been shown to have a median T_(max) ofmeloxicam that is less than about 90 minutes in fasted human subjects.23. The method of claim 1, wherein the oral dosage form has been shownto have a median T_(max) of meloxicam that is less than about 2 hours infasted human subjects.
 24. The method of claim 1, wherein the oraldosage form has been shown to have faster time to therapeutic plasmaconcentration in the human being as compared to the reference dosageform.